Anesthetic compounds and related methods of use

ABSTRACT

Provided herein are compounds according to formula (I): Provided herein is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier, and a method for providing anesthesia in a subject by administering such a pharmaceutical composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 National Phase Entry Application ofInternational Application No. PCT/US2013/021245 filed Jan. 11, 2013,which designates the U.S., and which claims benefit under 35 U.S.C.§119(e) of the U.S. Provisional Application No. 61/586,450, filed Jan.13, 2012, and U.S. Provisional Application No. 61/622,627, filed Apr.11, 2012, the content of both of which is incorporated herein byreference in its entirety.

GOVERNMENT SUPPORT

This invention was made with Government support under Grant No.R01-GM087316 awarded by the National Institutes of Health. TheGovernment has certain rights in the invention.

TECHNICAL FIELD

The disclosure relates to metomidate and etomidate analogues that haveimproved pharmacokinetic and pharmacodynamic properties, and their uses,for example as anaesthetics.

BACKGROUND

There is a great need for safer general anesthetics for use incritically ill patients, and particularly for patients with sepsis.(R)-Etomidate possesses many properties that would make it an idealanesthetic agent (e.g. high anesthetic potency, lesser effects oncardiovascular function and higher therapeutic index than other agents)if it were not such a potent inhibitor of adrenocortical function.

Etomidate is an imidazole-based intravenous hypnotic that is frequentlyused to induce anesthesia in the elderly and critically ill because itmaintains hemodynamic stability better than other anesthetic agents.¹⁻³Unfortunately, etomidate also produces adrenocortical suppression, aside effect that can persist for days after etomidate administration.⁴⁻⁸This potentially deadly side effect has caused clinicians to abandon theuse of etomidate infusions and led to concerns regarding theadministration of even a single intravenous (IV) bolus dose foranesthetic induction.⁹⁻¹¹ In a previous study, the inventors developedmethoxycarbonyl etomidate (MOC-etomidate) as the prototypical member ofa new class of “etomidate esters” that, similar to remifentanil andesmolol, contains a metabolically-labile ester moiety that is rapidlyhydrolyzed by esterases (FIG. 1).¹² Inventors showed that MOC-etomidateis rapidly hydrolyzed in rat blood and human liver s9 fraction andproduces hypnosis and adrenocortical suppression of extremely shortduration when administered to rats as an IV bolus.^(12,13)

A key feature of soft drugs is that their metabolic stabilities anddurations of action must fall within an optimal range to be clinicallyuseful.¹⁴ A drug that is too rapidly metabolized and short-acting willrequire the administration of impractically large quantities to maintaina therapeutic effect and may produce metabolite concentrationssufficient to produce undesirable side effects when given for aprolonged period of time. Conversely, a drug that is too slowlymetabolized and long acting will have pharmacokinetic properties thatare not meaningfully different from the metabolically stable “hard” drugfrom which it was derived.

Because esterase activity varies significantly among species, it isdifficult to predict from small animal studies whether any particularsoft drug's pharmacokinetic profile will fall within the optimal rangewhen administered to humans.¹⁵

SUMMARY

Provided herein are compounds according to formula (I):

-   -   wherein,    -   R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT;    -   R² is R¹, optionally substituted linear or branched C₁-C₁₀        alkyl, optionally substituted linear or branched C₂-C₁₀ alkenyl,        or optionally substituted linear or branched C₂-C₁₀ alkynyl;    -   each R₃ is independently halogen, CN, CF₃, SR², SOR², SO₂R²,        OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   Z is N or CR⁶;    -   R⁴, R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃,        SR², SOR², SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   R⁷ and R⁸ are independently hydrogen, optionally substituted        linear or branched C₁-C₁₀ alkyl, optionally substituted linear        or branched C₂-C₁₀ alkenyl, optionally substituted linear or        branched C₂-C₁₀ alkynyl, or R⁷ and R⁸ together with the carbon        they are attached to form an optionally substituted 3-8 membered        cyclyl or heterocyclyl;    -   R⁹ and R¹⁰ are independently hydrogen, optionally substituted        linear or branched C₁-C₁₀ alkyl, optionally substituted linear        or branched C₂-C₁₀ alkenyl, optionally substituted linear or        branched C₂-C₁₀ alkynyl, optionally substituted C₄-C₈ cyclyl,        optionally substituted C₃-C₈ heterocyclyl, or R⁹ and R¹⁰        together with the carbon they are attached to form an optionally        substituted 3-8 membered cyclyl or heterocyclyl, or R⁷ and R⁹        together with the carbons they are attached to form an        optionally substituted 3-8 membered cyclyl, heterocyclyl, aryl        or heteroaryl;    -   L¹ and L² are independently a bond, optionally substituted        linear or branched C₁-C₁₀ alkylene, optionally substituted        linear or branched C₂-C₁₀ alkenylene, or optionally substituted        linear or branched C₂-C₁₀ alkynylene;    -   T is H, optionally substituted linear or branched C₁-C₁₀ alkyl,        optionally substituted linear or branched C₂-C₁₀ alkenyl,        optionally substituted linear or branched C₂-C₁₀ alkynyl,        optionally substituted cyclyl, optionally substituted        heterocylcyl, optionally substituted aryl, optionally        substituted heteroaryl, or PEG, wherein the backbone of C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl can contain one or more        heteroatoms;    -   n is an integer from 0-5; and    -   p is 0 or 1, provided that at least one of R⁷, R⁸, R⁹ and R¹⁰ is        not hydrogen,    -   or a salt, solvate, or ester thereof.

Compounds of formula (I) are analogues of etomidate that retain(R)-etomidate's beneficial anesthetic properties, but do not causeclinically significant inhibition of adrenocortical function. However,unexpectedly compounds of formula (I) have improved enhanced duration ofaction as compared to etomidate analogues and derivatives described inPCT Publication No. WO 2011/005969 and US Patent Application PublicationNo. 2011/0053998. Accordingly, compounds of formula (I) have improvedpharmacokinetic and pharmacodynamic properties over (R)-etomidate thatallow for equivalent or improved anesthetic properties along with areduction in undesirable side effects.

In various cases, the compounds disclosed herein can have a structure offormula (IA), (IB), or (IC):

Also disclosed herein are methods of preparing compounds having astructure of formula (I) comprising coupling a compound of formula (II)and (a) a compound of formula (III) or (b) a compound of formula (IV):

wherein R², R³, R⁴, R⁵, R⁶, and n are as defined for formula (I) and Xis a carboxylic acid protecting group; removing X to form a carboxylicacid; coupling the carboxylic acid with an alcohol of structureHOL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT, wherein L², R⁷, R⁸, R⁹, R¹⁰, T and pare as defined for formula (I).

In another aspect, provided herein is a pharmaceutical anestheticcomposition, comprising an effective amount of a compound according toformula (I) and a pharmaceutically acceptable carrier.

Further disclosed herein are methods of providing anesthesia or sedationto a subject comprising administering to the subject an effective amountof a compound as disclosed herein. Also disclosed are uses of compoundsdisclosed herein as an anesthetic or sedative.

In yet still another aspect, provided herein is use of the compounds offormula (I) as described herein as a formulation for, or in themanufacture of a formulation for providing anesthesia or sedation in asubject in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows structures of various compounds.

FIG. 2 shows one approach to synthesis of compounds of formula (I).

FIG. 3 shows the nomenclature system for the compounds of formula (I).

FIG. 4 shows duration of anesthesia as a function of amount of etomidateanalogue administered.

FIG. 5 shows % drug remaining over time after incubation in rat blood.

FIG. 6 shows duration of anesthesia as a function of amount of etomidateanalogue administered in mouse.

FIG. 7 shows duration of anesthesia as a function of amount of etomidateanalogue administered in rat.

DETAILED DESCRIPTION

As mentioned above, because esterase activity varies significantly amongspecies, it is difficult to predict from small animal studies whetherany particular soft drug's pharmacokinetic profile will fall within theoptimal range when administered to humans. Early preclinical studiestypically use rodents, which are assumed to metabolize ester-containingdrugs much faster than humans and other large animals.¹⁶⁻¹⁸ However,that generality is not without exception and preliminary studies in dogsand monkeys indicated that methoxycarbonyl etomidate's duration ofaction in large animals is similar to that in rats (1-2 min). Thisindicates that methoxycarbonyl etomidate may be too short-acting forwidespread clinical use.

Thus, there is a need in the art to develop analogues of (R)-etomidatethat retain its many beneficial properties (e.g. rapid onset of action,little effect on blood pressure, high therapeutic index), but do notcause potentially dangerous inhibition of adrenocortical function andhave acceptable duration of action. Such analogues will permitanesthesia to be administered more safely to patients who are criticallyill.

This disclosure relates to safer analogues of etomidate that retain itsbeneficial characteristics (e.g. potent anesthetic, rapid onset ofanesthesia, little effect on blood pressures), but whose impact onadrenocortical steroid synthesis is substantially reduced. Certainembodiments include analogues of etomidate that are so rapidlymetabolized that inhibition of 11β-hydroxylase terminates shortly afterdiscontinuing anesthetic administration. For example, inhibition of11β-hydroxylase can terminate within about 2 hours, 1.5 hours, 1 hour,45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutesafter discontinuing anesthetic administration. The disclosed analoguesof etomidate bind with lower affinity to 11β-hydroxylase. For example,the disclosed analogues can bind to 11β-hydroxylase with an affinitythat is about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, 15%, 10% or less than the binding affinity ofetomidate to 11β-hydroxylase.

The compounds described herein can be understood as analogues ofetomidate (either R- or S-enantiomer) augmented with one or moreadditional metabolically-labile ester moieties attached to variouspositions of the core molecule directly or via various linker groups.Distal to the ester moieties, there can be a “tail” group (for example,—CH₃). The metabolically-labile ester groups can comprise one or twoalkyl, alkenyl, or alkynyl substituents on the a carbon or β carbon ofthe ester carbonyl group. Without wishing to be bound by a theory, thepresence of such a substituent is believed to reduce the rate ofhydrolysis of the ester thus increasing the duration of action of thecompound. The compounds described herein can also be understood asanalogues of etomidate (either R- or S-enantiomer) wherein the basicnitrogen in the imidazole ring has been replaced with a CH group.Without wishing to be bound by theory, it is believed that replacementof basic nitrogen with CH group reduces the binding affinity of thesecompounds for 11β-hydroxylase. These compounds can be further augmentedwith one or more additional metabolically-labile ester moieties attachedto various positions of the core molecule directly or via various linkergroups. Distal to the ester moieties, there can be a “tail” group (forexample, —CH₃). The metabolically-labile ester groups can comprise oneor two alkyl, alkenyl, or alkynyl substituents on the a carbon or βcarbon of the ester carbonyl group. The various embodiments of thesecompounds are discussed below.

In one aspect, provided herein are compounds according to formula (I):

-   -   wherein,    -   R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT;    -   R² is R¹, optionally substituted linear or branched C₁-C₁₀        alkyl, optionally substituted linear or branched C₂-C₁₀ alkenyl,        or optionally substituted linear or branched C₂-C₁₀ alkynyl;    -   each R₃ is independently halogen, CN, CF₃, SR², SOR², SO₂R²,        OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   Z is N or CR⁶;    -   R⁴, R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃,        SR², SOR², SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   R⁷ and R⁸ are independently hydrogen, optionally substituted        linear or branched C₁-C₁₀ alkyl, optionally substituted linear        or branched C₂-C₁₀ alkenyl, optionally substituted linear or        branched C₂-C₁₀ alkynyl, or R⁷ and R⁸ together with the carbon        they are attached to form an optionally substituted 3-8 membered        cyclyl or heterocyclyl;    -   R⁹ and R¹⁰ are independently hydrogen, optionally substituted        linear or branched C₁-C₁₀ alkyl, optionally substituted linear        or branched C₂-C₁₀ alkenyl, optionally substituted linear or        branched C₂-C₁₀ alkynyl, optionally substituted C₄-C₈ cyclyl,        optionally substituted C₃-C₈ heterocyclyl, or R⁹ and R¹⁰        together with the carbon they are attached to form an optionally        substituted 3-8 membered cyclyl or heterocyclyl, or    -   R⁷ and R⁹ together with the carbons they are attached to form an        optionally substituted 3-8 membered cyclyl, heterocyclyl, aryl        or heteroaryl;    -   L¹ and L² are independently a bond, optionally substituted        linear or branched C₁-C₁₀ alkylene, optionally substituted        linear or branched C₂-C₁₀ alkenylene, or optionally substituted        linear or branched C₂-C₁₀ alkynylene;    -   T is H, optionally substituted linear or branched C₁-C₁₀ alkyl,        optionally substituted linear or branched C₂-C₁₀ alkenyl,        optionally substituted linear or branched C₂-C₁₀ alkynyl,        optionally substituted cyclyl, optionally substituted        heterocylcyl, optionally substituted aryl, optionally        substituted heteroaryl, or PEG, wherein the backbone of C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl can contain one or more        heteroatoms;    -   n is an integer from 0-5; and    -   p is 0 or 1, provided that at least one of R⁷, R⁸, R⁹ and R¹⁰ is        not hydrogen.

The compounds of formula (I) include pharmaceutically acceptable salts,solvates, esters, stereoisomer mixtures, and enantiomers thereof.

Additional optional features of such compounds are described below, andare contemplated as further characterizing the compounds of formula (I)individually and/or in combination with each other, without limit.

In some embodiments, p is 0 or 1.

In various embodiments, the backbone of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ alkynyl can comprise one or more heteroatoms, such as O, N, or S.

In various cases, R² is an optionally substituted C₁-C₁₀ alkyl. In someembodiments, R² is selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl, hexyl,2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and2,2-dimethylbutyl. In some embodiments, R² is methyl or ethyl. In someembodiments R² can be an ester of R¹, such as CH₂CH₂C(O)OCH₃.

A skilled artisan recognizes that the carbon atom to which the R²substituent is attached is a chiral center. Therefore, the compound canbe in the form of a pure enantiomer. In some embodiments, the carbon towhich the R² substituent is attached is in the R configuration. In otherembodiments, the carbon to which the R² substituent is attached is inthe S configuration.

The variable n is an integer from 0 to 5. In some embodiments, n rangesfrom 0-3. In some specific embodiments, n is 0 or 1. In some morespecific embodiments, n is 0. Accordingly, when present, each of R³ isindependently halogen, halogen, CN, CF₃, SR², SOR², SO₂R², OR², CO₂H,CO₂R², N(R²)₂, NHR², NO₂, or R². In some cases, substituent R³ can behalogen or an electron withdrawing group. In some embodiments, R³ isfluorine or chlorine.

In some cases, R⁴ is hydrogen, halogen, CN or CF₃. In some embodiments,R⁴ is Br or CN.

In some embodiments, R⁵ is hydrogen.

In various cases, Z is N. In alternative cases, Z is CR⁶. In some cases,R⁶ is hydrogen, halogen, CN or CF₃. In some cases, R⁶ is hydrogen. Insome embodiments, R⁶ is Br or CN.

In some cases, at least one of R⁴ and R⁶ is Br or CN.

In various cases, R⁷ and R⁸ are independently hydrogen, optionallysubstituted C₁-C₁₀alkyl, optionally substituted C₄-C₆cyclyl oroptionally substituted C₄-C₆heterocyclyl; or R⁷ and R⁸ together with thecarbon they are attached to form a 3-, 4-, 5, or 6-membered cyclyl.

In various cases, R⁷ and R⁸ are independently hydrogen, optionallysubstituted linear or branched C₁-C₁₀ alkyl, optionally substitutedlinear or branched C₂-C₁₀ alkenyl, optionally substituted linear orbranched C₂-C₁₀ alkynyl.

In some embodiments, at least one of R⁷, R⁸, R⁹ and R¹⁰ is an optionallysubstituted linear or branched C₁-C₁₀ alkyl, optionally substitutedlinear or branched C₂-C₁₀alkenyl, or optionally substituted linear orbranched C₂-C₁₀ alkynyl. The C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀alkynyl backbone can comprise one or more heteroatoms, such as O, N, orS.

In some embodiments, at least one of R⁷, R⁸, R⁹ and R¹⁰ is an optionallysubstituted 3-8 membered cyclyl or heterocyclyl. Some specific examplesof the 3-8 membered cyclyl or heterocyclyl include phenyl, pyridyl,thiophene, furanyl, pyrazolyl, cyclohexyl, cyclohexenyl, cyclopentyl,cyclopentenyl, and piperdinyl.

In various cases, R⁷ and R⁸, R⁹ and R¹⁰ are independently hydrogen,optionally substituted linear or branched C₁-C₁₀ alkyl, optionallysubstituted linear or branched C₂-C₁₀ alkenyl, optionally substitutedlinear or branched C₂-C₁₀ alkynyl, provided that at least one of R⁷, R⁸,R⁹ and R¹⁰ is not a hydrogen, i.e., at least one of R⁷, R⁸, R⁹ and R¹⁰is an optionally substituted linear or branched C₁-C₁₀ alkyl, optionallysubstituted linear or branched C₂-C₁₀ alkenyl, or optionally substitutedlinear or branched C₂-C₁₀ alkynyl. The C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, orC₂-C₁₀ alkynyl backbone can comprise one or more heteroatoms, such as O,N, or S.

In some embodiments, R⁷, R⁸, R⁹ and R¹⁰ are selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and2,2-dimethylbutyl.

R⁹ and R¹⁰ can be different or can be both the same. In someembodiments, one of R⁹ and R¹⁰ is hydrogen and the other is anoptionally substituted linear or branched C₁-C₁₀ alkyl. In someembodiments, one of R⁹ and R¹⁰ is methyl, ethyl, propyl, or isopropyl.In some embodiments, R⁹ and R¹⁰ are both methyl. In some embodiments, R⁹and R¹⁰ together with the carbon they are attached to form a 3 memberedring.

A skilled artisan would recognize that when R⁹ and R¹⁰ are different,the carbon to which they are attached to can be in the R or Sconfiguration. Accordingly, in some embodiments, the carbon to which R⁹and R¹⁰ are attached is in the R configuration. In some otherembodiments, the carbon to which R⁹ and R¹⁰ are attached is in the Sconfiguration.

When present, R⁷ and R⁸ can be different or can be the same. In someembodiments, one of R⁷ and R⁸ is hydrogen and the other is an optionallysubstituted linear or branched C₁-C₁₀ alkyl. In some embodiments, one ofR⁷ and R⁷ is methyl, ethyl, propyl, or isopropyl. In some embodiments,R⁷ and R⁸ are both methyl. In some embodiments, R⁷ and R⁸ together withthe carbon they are attached to form a 3 membered ring.

Similar to R⁹ and R¹⁰, when R⁷ and R⁸ are different, the carbon to whichthey are attached to can be in the R or S configuration. Accordingly, insome embodiments, the carbon to which R⁷ and R⁸ are attached is in the Rconfiguration. In some other embodiments, the carbon to which R⁸ and R⁸are attached is in the S configuration.

In some cases, R⁷ and R⁸ are independently hydrogen, optionallysubstituted linear or branched C₁-C₁₀alkyl, C₂-C₁₀alkenyl, orC₂-C₁₀alkynyl. In various cases, R⁷ and R⁹ taken together form anoptionally substituted 3-8 membered carbocyclyl, heterocyclyl, aryl, orheteroaryl.

In various cases, L¹ is a bond, optionally substituted linear orbranched C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; whereinthe backbone of C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynyleneoptionally comprises one or more heteroatoms. In various cases, L² is abond, optionally substituted linear or branched C₁-C₁₀alkylene,C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; wherein the backbone ofC₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene optionallycomprises one or more heteroatoms.

Preferably, L¹ and L² are each independently a bond or a linear C₁-C₄alkylene group. In some embodiments, L¹ is a bond or CH₂CH₂. In someembodiments, L² is CH₂CH₂, CH₂(CH₂)₄CH₂, or CH₂CH₂O(CH₂)₃. In someembodiments, L² is a bond. In some embodiments, both of L¹ and L² are abond.

The tail T can be hydrogen or an optionally substituted linear orbranched C₁-C₁₀ alkyl, optionally substituted linear or branched C₂-C₁₀alkenyl, optionally substituted linear or branched C₂-C₁₀ alkynyl,optionally substituted cyclyl, optionally substituted heterocylcyl,optionally substituted aryl, optionally substituted heteroaryl, or PEG.The backbone of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl can containone or more heteroatoms, such as O, N, or S. In some cases, T is a C₁-C₄alkyl group. In some embodiments, T is an optionally substituted methyl,ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl, hexyl,2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, or2-hydroxypropyl. The tail T can also be an electron donating group. Insome embodiments, T is hydrogen, methyl, nitrophenol or 2-hydroxypropyl.

In various cases, T is optionally substituted C₁-C₁₀ alkyl, andspecifically contemplated T include methyl and ethyl. In various cases,T is optionally substituted cyclyl or heterocyclyl, and specificallycontemplated T include cyclopropyl, cyclobutyl, oxetanyl, morpholinyl,and oxazolindinyl.

In various cases, L is an optionally substituted linear or branchedC₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; wherein thebackbone of C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynyleneoptionally comprises one or more heteroatoms. In various cases, L² is anoptionally substituted linear or branched C₁-C₁₀alkylene,C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; wherein the backbone ofC₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene optionallycomprises one or more heteroatoms.

In some embodiments, R¹ is -L²-CH₂CH(CH₃)—, -L²-CH₂C(CH₃)₂—,-L²-CH₂CH(CH(CH₃)₂)—,

-L²-CH(CH₃)CH₂—, -L²-C(CH₃)₂CH₂—, -L²-CH(CH(CH₃)₂)CH2-, -L²-CH(CH₃)—,-L²-C(CH₃)₂—, -L²-CH(CH(CH₃)₂)—, , —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH(CH(CH₃)₂)—,

—CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, —CH(CH(CH₃)₂)CH2-, —CH(CH₃)—, —C(CH₃)₂—, or—CH(CH(CH₃)₂)—.

The compounds of formula (I) can include pharmaceutically acceptablesalts, stereoisomer mixtures, and enantiomers thereof. The compounds canalso include physiologically acceptable salts of the compounds offormula (I). Preferred physiologically acceptable salts areacid-addition salts known to those of skill in the art. Commonphysiologically acceptable acid-addition salts include but are notlimited to, hydrochloric acid salts, oxalate salts, and tartrate salts.

In some embodiments, R¹ and R² are a bond, and p is 0.

In some other embodiments, R¹ and R² are a bond, and p is 1.

When p is 0, none or one of R⁹ and R¹⁰ can be hydrogen. For example,when p is 0, one of R⁹ and R¹⁰ is hydrogen and the other can be methylor isopropyl. In another example, when p is 0, both of R⁹ and R¹⁰ aremethyl. In yet another example, when p is 0, R⁹ and R¹⁰ together withthe carbon to which they are attached form a three membered ring, suchas cyclopropyl.

When p is 1, none, one, two or three of R⁷, R⁸, R⁹ and R¹⁰ can behydrogen. When only two of R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, the twohydrogens can be attached to the same carbon, i.e., both of R⁷ and R⁸are hydrogen or both of R⁹ and R¹⁰ are hydrogen. Without limitations,all combinations of hydrogen locations for R⁷, R⁸, R⁹ and R¹⁰ areconsidered herein. For example, both of R⁷ and R⁸ are hydrogen and oneor both of R⁹ and R¹⁰ are not hydrogen or both of R⁹ and R¹⁰ arehydrogen and one or both of R⁷ and R⁸ are not hydrogen. Accordingly, insome embodiments, R⁷, R⁸, and one of R⁹ and R¹⁰ are all hydrogen. Insome other embodiments, R⁹, R¹⁰, and one of R⁷ and R⁸ are all hydrogen.

In some embodiments, when p is 1, R⁷ and R⁸ are both hydrogen and one ofR⁹ and R¹⁰ is methyl or isopropyl and the other is hydrogen. In someother embodiments, when p 1 is 1, R⁷ and R⁸ are both hydrogen and R⁹ andR¹⁰ are same or together with the carbon to which they are attached forma three membered ring. For example, R⁷ and R⁸ are both hydrogen and R⁹and R¹⁰ are both methyl.

In some other embodiments, when p is 1, R⁹ and R¹⁰ are both hydrogen andone of R⁷ and R⁸ is methyl or isopropyl and the other is hydrogen. Inyet some other embodiments, when p 1 is 1, R⁹ and R¹⁰ are both hydrogenand R⁷ and R⁸ are same or together with the carbon to which they areattached form a three membered ring. For example, R⁹ and R¹⁰ are bothhydrogen and R⁷ and R⁸ are both methyl.

When present, R⁶ can be the same or different from R⁴ or R⁵. Forexample, R⁴, R⁵′ and R⁶ and all can be hydrogen; only two of R⁴, R⁵′ andR⁶ can be hydrogen; only one of R⁴, R⁵′ and R⁶ can be hydrogen; or noneof R⁴, R⁵′ and R⁶ can be hydrogen. For example, R⁴ and R⁶ can both behydrogen. In another example, one of R⁴ and R⁶ can be a halogen or CNand the other can be hydrogen. Accordingly, in some embodiments, R⁶ is Hand R⁴ is Br or CN. In some other embodiments, R⁴ is H and R⁶ is Br orCN.

Similarly, when R⁶ is absent, i.e., Z is N, R⁴ and R⁵ can be the same ordifferent. In one embodiment, Z is N and R⁴ and R⁵ are hydrogen.

Compounds of formula (I) preferably have the same stereochemistry as(R)-etomidate. R², R³, L¹, L², and T can be branched hydrocarbon chains,however, not to the extent that steric hindrance or conjugationinterferes with the desired activity.

In certain embodiments, the compound includes two or more ester groups.Suitable ester-containing groups (e.g. linker-ester-tail or ester-tail)can be added to the bridging carbon or at various positions of thephenyl ring or the core molecule.

In various cases, the compound disclosed herein has a structure offormula (IA), (TB), or (IC):

In some embodiments, the compound of formula (I) is selected from thegroup consisting of α-R-methyl-MOC-etomidate, α-S-methyl-MOC-etomidate,α-dimethyl-MOC-etomidate, β-R-methyl-MOC-etomidate,β-S-methyl-MOC-etomidate, β-dimethyl-MOC-etomidate,R-methyl-MOC-metomidate, S-methyl-MOC-metomidate,dimethyl-MOC-metomidate, S-isopropyl-MOC-metomidate,R-isopropyl-MOC-metomidate, cyclopropyl-MOC-metomidate, andpharmaceutically acceptable salts, stereoisomer mixtures, andenantiomers thereof. Structures of the above etomidate analogues areshown in Table 1 in the Examples section below.

Carboetomidate is an analogue of etomidate wherein the basic nitrogen inthe imidazole ring is replaced by a CH group. Similarly, carbometomidateis an analogue of metomidate wherein the basic nitrogen in the imidazolering is replaced by a CH group. Accordingly, in some embodiments, acompound of formula (I) is a carboetomidate analogue.

In some embodiments, the compound of formula (I) is selected from thegroup consisting of

(α-R-methyl-MOC-carboetomidate),

(α-S-methyl-MOC-carboetomidate),

(α-dimethyl-MOC-carboetomidate),

(β-R-methyl-MOC-carboetomidate),

(β-S-methyl-MOC-carboetomidate),

(β-dimethyl-MOC-carboetomidate),

(R-methyl-MOC-carbometomidate),

(S-methyl-MOC-carbometomidate),

(dimethyl-MOC-carbometomidate),

(S-isopropyl-MOC-carbometomidate),

(R-isopropyl-MOC-carbometomidate),

(cyclopropyl-MOC-carbometomidate), and pharmaceutically acceptablesalts, stereoisomer mixtures, and enantiomers thereof.

Other exemplary compounds of formula (I) include:

Other compounds specifically contemplated include:

Still other compounds contemplated include:

Etomidate analogues with ester moieties on carboetomidate (etomidatewith the basic nitrogen in the imidazole ring replaced by CR⁶) that aresterically unhindered and/or electronically isolated from the pielectron systems in the imidazole and phenyl rings are also preferred.

Compounds of formula (I) can be analogues of etomidate that retain(R)-etomidate's beneficial anesthetic properties, but do not causeclinically significant inhibition of adrenocortical function. Forexample, the disclosed analogues inhibit adrenocortical function lessthan 95%, 90%, 85%, 80%, 75%, 70%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,40%, 35%, 30%, 25%, 20%, 15%, or 10% relative to inhibition ofadrenocortical function by a similar amount of etomidate or an etomidateanalogue or derivative described in PCT Publication No. WO 2011/005969and US Patent Application Publication No. 2011/0053998. In anotherexample, the disclosed analogues inhibit adrenocortical function in anamount that is from about 10% to 90%, 15% to 85%, 20% to 80%, 25% to75%, 30% to 70%, 35% to 65%, 40% to 60%, 45% to 55% to the inhibition ofadrenocortical function by a similar amount of etomidate or an etomidateanalogue or derivative described in PCT Publication No. WO 2011/005969and US Patent Application Publication No. 2011/0053998.

Further, unexpectedly, compounds of formula (I) can have improvedenhanced duration of action as compared to etomidate analogues andderivatives described in PCT Publication No. WO 2011/005969 and USPatent Application Publication No. 2011/0053998. For example, thedisclosed analogues can Etomidate analogues shown in PCT Publication No.WO 2011/005969 and US Patent Application Publication No. 2011/0053998have ester moieties that are believed to be highly susceptible tohydrolysis by esterases. See U.S. Pat. No. 3,354,173; U.S. Pat. No.5,466,700; U.S. Pat. No. 5,019,583; and U.S. Patent Publication No. US2003/0055023. Accordingly, they act like other ultra-short acting drugslike remifentanil and esmolol, and have very short duration of action.For example, the disclosed analogues can have a duration of action thatis

The term “duration of action” refers herein to the length of time ananesthetic exhibits a desired pharmacologic effect after administration.This is determined by the amount of time drug concentration is at orabove the minimum effective concentration. The duration of drug in thebody is not equivalent to the duration of effect. A drug can be in thebody for a period of time that is much longer than the duration ofaction, if the concentration remains below the minimum effectiveconcentration. In fact, some drugs that are slowly absorbed may neverexert a pharmacologic effect, even though they are in the body for aprolonged period of time. This occurs when the drug is absorbed soslowly that it never reaches concentrations that meet or exceed theminimum effective concentration.

By “improved duration of action” is meant duration of action that lastsfor a longer period of time relative to a control or reference. Forexample, the disclosed analogues can have a duration of action that is 5minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2hours, 3 hours, 4 hours, 5 hours, 6 hours or longer than a control orreference. A control or reference can be duration of action of etomidateor etomidate analogues and derivatives described in PCT Publication No.WO 2011/005969 and US Patent Application Publication No. 2011/0053998.In another example, the disclosed analogues can have duration of actionthat lasts for a period of 10 minutes, 15 minutes, 20 minutes, 25minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours,18 hours, 24 hours or longer.

By “short duration of action” is meant duration of action that lasts fora shorter period of time. For example, the disclosed analogues can havea duration of action of 10 seconds, 15 seconds, 20 seconds, 35 seconds,30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds,1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25minutes, 20 minutes, 35 minutes, 30 minutes, 45 minutes, 40 minutes, 55minutes, 1 hour, 2 hours, 4 hours, 5 hours, 6 hours or less.

Additionally, the sedative/anesthetic effects of compounds describedherein can wear off quickly. The term “wear off” in relation tosedative/anesthetic effect means that the administered compound nolonger exhibits a pharmacologic effect on the subject. For example, thedisclosed compounds show little or no pharmacologic effects after 30seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5 hours, 6 hours, 12 hours or 24 hours after discontinuinganesthetic administration.

Accordingly, a subject can be continually infused to keep the subjectsedated during medical procedure, e.g. surgery. However, the subject canwake up quickly once the infusion is stopped. For example, the subjectcan wake up within about 2 hours, 1.5 hours, 1 hour, 45 minutes, 30minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes afterdiscontinuing anesthetic administration.

The R², T, L¹, and L² substituents can each independently be substitutedwith one or more electron donating groups. In embodiments, the electrondonating group can be an alkyl or 1-alkenyl. Other electron donatinggroups such as hydroxyl, amino, NHC(O)R, OC(O)R and aryls andheteroaryls can also be used. The presence of electron donating groupsserves to decrease the partial positive charge on the ester carbonylatom, thereby decreasing susceptibility to nucleophilic attack byesterases and reducing rate of hydrolysis by esterases. Inventors havediscovered that etomidate analogues with rapidly hydrolyzed esters haveshort duration of action. However, by decreasing the rate of esterhydrolysis, duration of action can be increased.

A compound according to the description herein can be characterized byanesthetic activity and enhanced GABA_(A) receptor activity. TheGABA_(A) receptor is an ionotropic receptor and ligand-gated ionchannel. Its endogenous ligand is γ-aminobutyric acid (GABA), the majorinhibitory neurotransmitter in the central nervous system. Uponactivation, the GABAA receptor selectively conducts Cl— through itspore, resulting in hyperpolarization of the neuron. This causes aninhibitory effect on neurotransmission by diminishing the chance of asuccessful action potential occurring. In some embodiments, thedisclosed analogues can increase GABA_(A) receptor activity by at least1.1×, 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, 4.5×, 5×, 5.5×, 10×, 15×, 20× orlonger than that of etomidate or an etomidate analogue or derivativedescribed in PCT Pub. No. WO 2011/005969 and US Pat. App. Pub. No.2011/0053998.

A compound according to the description herein can be characterized bypotent in vitro and in vivo anesthetic activity and enhanced GABA_(A)receptor effects. A compound according to the description herein can becharacterized by being a GABA_(A) receptor agonist. A compound accordingto the description herein can be characterized by reduced inhibitoryactivity with respect to in vitro and in vivo adrenocortical steroidsynthesis and/or good duration of anesthetic action. In addition, acompound according to the description herein can have a longer durationof anesthetic action than those described, for example, in PCT Pub. No.WO 2011/005969 and US Pat. App. Pub. No. 2011/0053998.

The term “duration of anesthesia” or “duration of anesthetic action”means the period of time during which the administered compound exhibitsa pharmacologic effect on the subject or the period of time during whichthe compound measurably blocks nerve conduction. Without limitation, thedisclosed analogues can have a duration of anesthetic action for aperiod of 30 minutes, 1 hour, 2 hours, 4 hours, 4 hours, 5 hours, 6hours, 12 hours, 18 hours, 24 hours or longer. In some embodiments, thedisclosed analogues can have a duration of anesthetic action that is atleast 1.1×, 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, 4.5×, 5×, 5.5×, 10×, 15×, 20×or longer than that of etomidate or an etomidate analogue or derivativedescribed in PCT Pub. No. WO 2011/005969 and US Pat. App. Pub. No.2011/0053998.

The new compounds described herein can be administered either alone inthe form of mixtures with one another, or in combination with acceptablepharmaceutical carriers. Thus, pharmaceutical compositions which cancomprise an effective amount of at least one compound of thedescription, with or without a pharmaceutically or physiologicallyacceptable carrier, are also contemplated. If appropriate, the compoundcan be administered in the form of a physiologically acceptable salt,for example, an acid-addition salt.

Described herein also is a method of treating animals or humans. Thismethod comprises administering to the animal or person an effectiveamount of at least one of the compounds described herein, or apharmaceutically acceptable salt or solvate thereof, with, or without apharmaceutically acceptable carrier. Intravenous administration ofetomidate is well known and described, for example in U.S. Pat. No.4,289,783, the content of which is incorporated herein by reference inits entirety. Such intravenous methods of administration are applicableto the compounds described herein.

Disclosed here is a potent sedative hypnotic that does not significantlysuppress adrenocortical function and can be used to produce and/ormaintain anesthesia, sedation, or otherwise lower central nervous systemexcitability. It can exhibit one or more of the following beneficialproperties as compared to alternative agents: higher potency, longerduration of therapeutic action, shorter duration of side effects,reduced adrenocortical suppression, higher therapeutic index, lowertoxicity, reduced cardiovascular depression, and greater ease oftitration to desired effect.

In some embodiments, the disclosed analogues have a potency that is atleast 1.1×, 1.2×, 1.3×, 1.4×, 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, 4.5×, 5×,10×15×, 20×, 25×, 30×, 50× or higher than the potency of a similaramount of etomidate or an etomidate analogue or derivative described inPCT Pub. No. WO 2011/005969 and US Pat. App. Pub. No. 2011/0053998. Insome embodiments, the disclosed analogues have a duration of therapeuticaction that is at least 1.1×, 1.2×, 1.3×, 1.4×, 1.5×, 2×, 2.5×, 3×,3.5×, 4×, 4.5×, 5×, 10×15×, 20×, 25×, 30×, 50× or longer than durationof therapeutic action of a similar amount of etomidate or an etomidateanalogue or derivative described in PCT Pub. No. WO 2011/005969 and USPat. App. Pub. No. 2011/0053998. In some embodiments, the disclosedanalogues have a therapeutic index that is at least 1.1×, 1.2×, 1.3×,1.4×, 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, 4.5×, 5×, 10×15×, 20×, 25×, 30×, 50×or higher than the therapeutic index of etomidate or an etomidateanalogue or derivative described in PCT Pub. No. WO 2011/005969 and USPat. App. Pub. No. 2011/0053998. In some embodiments, the disclosedanalogues have a shorter duration of side effects relative to etomidateor an etomidate analogue or derivative described in PCT Pub. No. WO2011/005969 and US Pat. App. Pub. No. 2011/0053998. For example, theduration of side effects of the disclosed analogues can be period oftime which is at least 1 minute, 5 minutes, 10 minutes, 15 minutes, 20minutes, 35 minutes, 30 minutes, 35 minutes, 10 minutes, 45 minutes, 50minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hour,12 hours, 18 hours, 24 hours shorter than the duration of side effectsby a similar amount of etomidate or an etomidate analogue or derivativedescribed in PCT Pub. No. WO 2011/005969 and US Pat. App. Pub. No.2011/0053998. In some embodiments, the disclosed analogues inhibitadrenocortical function less than 95%, 90%, 85%, 80%, 75%, 70%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%relative to inhibition of adrenocortical function by a similar amount ofetomidate or an etomidate analogue or derivative described in PCTPublication No. WO 2011/005969 and US Patent Application Publication No.2011/0053998. In some embodiments, the disclosed analogues havecardiovascular depression that is less than 95%, 90%, 85%, 80%, 75%,70%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or10% relative to the cardiovascular depression by a similar amount ofetomidate or an etomidate analogue or derivative described in PCTPublication No. WO 2011/005969 and US Patent Application Publication No.2011/0053998. In some embodiments, the disclosed analogues have toxicitythat is less than 95%, 90%, 85%, 80%, 75%, 70%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% relative to the toxicityof a similar amount of etomidate or an etomidate analogue or derivativedescribed in PCT Publication No. WO 2011/005969 and US PatentApplication Publication No. 2011/0053998

The compounds described herein can be administered as a single IV bolusand/or a continuous IV infusion. Other routes of delivery can includeoral, rectal, transmucosal, subcutaneous, or inhaled, for example.

Pharmaceutical Compositions

For administration to a subject, the compounds described herein can beprovided in pharmaceutically acceptable (e.g., sterile) compositions.Accordingly, another aspect described herein is a pharmaceuticalcomposition comprising a compound according to formula (I) and apharmaceutically acceptable carrier. These pharmaceutically acceptablecompositions comprise an effective amount of one or more of thecompounds described herein, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents. Asdescribed in detail below, the pharmaceutical compositions of thepresent disclosure can be specially formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), lozenges, dragees, capsules, pills, tablets(e.g., those targeted for buccal, sublingual, and/or systemicabsorption), boluses, powders, granules, pastes for application to thetongue; (2) parenteral administration, for example, by subcutaneous,intramuscular, intravenous (e.g., bolus or infusion) or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8)transmucosally; or (9) nasally. Additionally, compounds can be implantedinto a patient or injected using a drug delivery system. See, forexample, Urquhart, et al., Ann. Rev. Pharmacol. Toxicol. 24: 199-236(1984); Lewis, ed. “Controlled Release of Pesticides andPharmaceuticals” (Plenum Press, New York, 1981); U.S. Pat. No.3,773,919; and U.S. Pat. No. 3,270,960, content of all of which isherein incorporated by reference.

Formulations can optionally further comprise one or more cylcodextrins.In various cases, cyclodextrins are α-cyclodextrins, β-cyclodextrins,γ-cyclodextrins, and/or δ-cyclodextrins. In some embodiments, thecyclodextrins are modified cyclodextrins. Specific modificationsinclude, but are not limited to, hydroxyalkyl ethers and sulfoalkylethers. In some embodiments, the modified cyclodextrins aresulfobutylether-1-β-cyclodextrin, sulfobutylether-4-β-cyclodextrin,sulfobutylether-7-β-cyclodextrin, and/or hydroxypropyletherβ-cyclodextrin. In one embodiment, the modified cyclodextrin comprisessulfobutylether-7-β-cyclodextrin.

As used herein, the term “pharmaceutically acceptable” or“pharmacologically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio. Moreover, for animal (e.g., human)administration, it will be understood that compositions should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Biological Standards.

As used herein, the term “pharmaceutically-acceptable carrier” means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, methylcellulose, ethyl cellulose,microcrystalline cellulose and cellulose acetate; (4) powderedtragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such asmagnesium stearate, sodium lauryl sulfate and talc; (8) excipients, suchas cocoa butter and suppository waxes; (9) oils, such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12)esters, such as ethyl oleate and ethyl laurate; (13) agar; (14)buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents,such as polypeptides and amino acids (23) serum component, such as serumalbumin, HDL and LDL; (22) C₂-C₁₂ alcohols, such as ethanol; and (23)other non-toxic compatible substances employed in pharmaceuticalformulations. Wetting agents, coloring agents, release agents, coatingagents, disintegrating agents, binders, sweetening agents, flavoringagents, perfuming agents, protease inhibitors, plasticizers,emulsifiers, stabilizing agents, viscosity increasing agents, filmforming agents, solubilizing agents, surfactants, preservative andantioxidants can also be present in the formulation. The terms such as“excipient”, “carrier”, “pharmaceutically acceptable carrier” or thelike are used interchangeably herein.

For liquid formulations, pharmaceutically acceptable carriers can beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions, orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil. Solutions or suspensions can also include one or more ofthe following components: a sterile diluent, including water forinjection, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol and other synthetic solvents; antibacterial agents,including benzyl alcohol and methyl parabens; antioxidants, includingascorbic acid or sodium bisulfite; chelating agents, includingethylenediaminetetraacetic acid (EDTA); buffers, including acetates,citrates and phosphates, and agents for the adjustment of tonicity,including sodium chloride and dextrose. The pH can be adjusted withacids or bases, including hydrochloric acid and sodium hydroxide.

Liposomes and non-aqueous vehicles such as fixed oils may also be used.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active compound, use thereof in thecompositions is contemplated. Supplementary active compounds can also beincorporated into the compositions.

As indicated above, the compositions can further comprise binders (e.g.,acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g., cornstarch, potato starch, alginic acid,silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodiumstarch glycolate, Primogel), buffers (e.g., tris-HCl, acetate,phosphate) of various pH and ionic strength, additives such as albuminor gelatin to prevent absorption to surfaces, detergents (e.g., Tween20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol), a glidant(e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosityincreasing agents (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citricacid), flavoring agents (e.g., peppermint, methyl salicylate, or orangeflavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens),lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol,sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In some embodiments, the compounds of the present disclosure can be usedin the form of a pharmaceutically acceptable salt. As used herein, theterm “pharmaceutically-acceptable salts” refers to the conventionalnontoxic salts or quaternary ammonium salts of compounds describedherein, e.g., from non-toxic organic or inorganic acids. These salts canbe prepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting a compound describedherein in its free base or acid form with a suitable organic orinorganic acid or base, and isolating the salt thus formed duringsubsequent purification. Conventional nontoxic salts include thosederived from inorganic acids such as sulfuric, sulfamic, phosphoric,nitric, and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic,and the like. See, for example, Berge et al., “Pharmaceutical Salts”, J.Pharm. Sci. 66:1-19 (1977), the content of which is herein incorporatedby reference in its entirety. Exemplary salts also include thehydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, succinate, valerate, oleate, palmitate, stearate, laurate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate,and laurylsulphonate salts and the like.

Suitable acids which are capable of forming salts with the compounds ofthe disclosure include inorganic acids such as hydrochloric acid,hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid,sulfuric acid, phosphoric acid, and the like; and organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, anthranilic acid, cinnamic acid, naphthalene sulfonicacid, sulfanilic acid, trifluoroacetic acid, methansulfonic acid,benzenesulfonic acid, p-toulenesulfonic acid, and the like. Suitablebases capable of forming salts with the compounds of the disclosureinclude inorganic bases such as sodium hydroxide, ammonium hydroxide,potassium hydroxide and the like; and organic bases such as mono-, di-and tri-alkyl and aryl amines (e.g., triethylamine, diisopropyl amine,methyl amine, dimethyl amine, pyridine, picoline, dicyclohexylamine,N,N′-dibezylethylenediamine, and the like) and optionally substitutedethanol-amines (e.g., ethanolamine, diethanolamine, trierhanolamine andthe like).

It is especially advantageous to formulate oral and intravenouscompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals. The pharmaceutical compositions can beincluded in a container, pack, or dispenser together with instructionsfor administration.

The amount of a compound described herein that can be combined with acarrier material to produce a single dosage form will generally be aneffective amount of the compound. A pharmaceutical composition typicallycontains an amount of at least 0.01 weight % of active ingredient, i.e.,a compound of this disclosure, per weight of total pharmaceuticalcomposition. Generally out of one hundred percent, this amount willrange from about 0.01% to 99% of the compound, preferably from about 5%to about 70%, most preferably from 10% to about 30%. A weight % is aratio by weight of active ingredient to total composition. Thus, forexample, 0.1 weight % is 0.1 grams of the compound per 100 grams oftotal composition.

The preparation of pharmaceutical compositions that contain an activecomponent is well understood in the art, for example, by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the active agents are mixed with additives customary forthis purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic, or oily solutions and the like as detailed above.

For intravenous administration, glucuronic acid, L-lactic acid, aceticacid, citric acid or any pharmaceutically acceptable acid/conjugate basewith reasonable buffering capacity in the pH range acceptable forintravenous administration can be used as buffers. Sodium chloridesolution wherein the pH has been adjusted to the desired range witheither acid or base, for example, hydrochloric acid or sodium hydroxide,can also be employed. Typically, a pH range for the intravenousformulation can be in the range of from about 5 to about 12.

Subcutaneous formulations can be prepared according to procedures wellknown in the art at a pH in the range between about 5 and about 12,which include suitable buffers and isotonicity agents. They can beformulated to deliver a daily dose of the active agent in one or moredaily subcutaneous administrations. The choice of appropriate buffer andpH of a formulation, depending on solubility of one or more compounds tobe administered, is readily made by a person having ordinary skill inthe art. Sodium chloride solution wherein the pH has been adjusted tothe desired range with either acid or base, for example, hydrochloricacid or sodium hydroxide, can also be employed in the subcutaneousformulation. Typically, a pH range for the subcutaneous formulation canbe in the range of from about 5 to about 12.

Described herein are also a method for providing anesthesia in a subjectcomprising administering to the subject a compound of formula (I) or apharmaceutical composition as described herein, and use of a compound offormula (I) or a pharmaceutical composition as described hereinproviding anesthesia in a subject or in manufacture of a medicament forproviding anesthesia in a subject. Also contemplated is use of acompound of formula (I) as a potentiator of GABA_(A) receptor/channelactivation. Accordingly, in certain embodiments, the method includesadministering an effective dose of the compound. As used herein, theterm “effective dose” or “effective amount” is meant that amountsufficient to elicit the desired pharmacological effects at a reasonablebenefit/risk ratio applicable to any medical treatment.

Described herein are also a method for providing anesthesia in a subjectcomprising administering to the subject a compound of formula (I) or apharmaceutical composition as described herein, and use of a compound offormula (I) or a pharmaceutical composition as described herein toalleviate pain in, or provide an analgesic to, a subject or in themanufacture of a medicament for alleviating pain or providing ananalgesic to a subject. Accordingly, in certain embodiments, the methodincludes use or administration of an effective dose of the compound. Asused herein, the term “effective dose” or “effective amount” is meantthat amount sufficient to elicit the desired pharmacological effects ata reasonable benefit/risk ratio applicable to any medical treatment.

Determination of an effective amount is well within the capability ofthose skilled in the art. Generally, the actual effective amount canvary with the specific compound, the use or application technique, thedesired effect, the duration of the effect and side effects, thesubject's history, age, condition, sex, as well as the severity and typeof the medical condition in the subject, and administration of otherpharmaceutically active agents. Accordingly, an effective dose ofcompound described herein is an amount sufficient to induce and maintaingeneral anesthesia or conscious sedation in a subject.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of use or administration utilized.

The effective dose can be estimated initially from cell culture assays.A dose may be formulated in animal models to achieve a circulatingplasma concentration range that includes the IC50 (i.e., theconcentration of the therapeutic which achieves a half-maximalinhibition of symptoms) as determined in cell culture. Levels in plasmamay be measured, for example, by high performance liquid chromatography.The effects of any particular dosage can be monitored by a suitablebioassay. The effective plasma concentration for inducing anesthesiausing a compound as disclosed herein can be about 0.01 μM to about 10μM, about 0.2 μM to about 5 μM, or about 0.8 to about 3 μM in a subject,such as a rat, dog, or human.

Generally, the compositions are administered so that a compound of thedisclosure herein is used or given at a dose from 1 μg/kg to 1000 mg/kg;1 μg/kg to 500 mg/kg; 1 μg/kg to 150 mg/kg, 1 μg/kg to 100 mg/kg, 1μg/kg to 50 mg/kg, 1 μg/kg to 20 mg/kg, 1 μg/kg to 10 mg/kg, 1 μg/kg to1 mg/kg, 100 μg/kg to 100 mg/kg, 100 μg/kg to 50 mg/kg, 100 μg/kg to 20mg/kg, 100 μg/kg to 10 mg/kg, 100 μg/kg to 1 mg/kg, 1 mg/kg to 100mg/kg, 1 mg/kg to 50 mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 10 mg/kg, 10mg/kg to 100 mg/kg, 10 mg/kg to 50 mg/kg, or 10 mg/kg to 20 mg/kg. It isto be understood that ranges given here include all intermediate ranges,for example, the range 1 mg/kg to 10 mg/kg includes 1 mg/kg to 2 mg/kg,1 mg/kg to 3 mg/kg, 1 mg/kg to 4 mg/kg, 1 mg/kg to 5 mg/kg, 1 mg/kg to 6mg/kg, 1 mg/kg to 7 mg/kg, 1 mg/kg to 8 mg/kg, 1 mg/kg to 9 mg/kg, 2mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 4 mg/kg to 10 mg/kg, 5 mg/kg to10 mg/kg, 6 mg/kg to 10 mg/kg, 7 mg/kg to 10 mg/kg, 8 mg/kg to 10 mg/kg,9 mg/kg to 10 mg/kg, and the like. Further contemplated is a dose(either as a bolus or continuous infusion) of about 0.1 mg/kg to about10 mg/kg, about 0.3 mg/kg to about 5 mg/kg, or 0.5 mg/kg to about 3mg/kg. It is to be further understood that the ranges intermediate tothose given above are also within the scope of this disclosure, forexample, in the range 1 mg/kg to 10 mg/kg, for example use or doseranges such as 2 mg/kg to 8 mg/kg, 3 mg/kg to 7 mg/kg, 4 mg/kg to 6mg/kg, and the like.

The compound can be administered as a single bolus or multiple boluses,as a continuous infusion, or a combination thereof. For example, thecompound can be administered as a single bolus initially, and thenadministered as a continuous infusion following the bolus. The rate ofthe infusion can be any rate sufficient to affect anesthesia orsedation. Some contemplated infusion rates include from 1 μg/kg/min to100 mg/kg/min, or from 1 μg/kg/hr to 1000 mg/kg/hr. Rates of infusioncan include 0.2 to 1.5 mg/kg/min, or more specifically 0.25 to 1mg/kg/min, or even more specifically 0.25 to 0.5 mg/kg/min. It will beappreciated that the rate of infusion can be determined based upon thedose necessary to induce sedation or anesthesia and the rate ofelimination of the compound, such that the compound is administered viainfusion at a rate sufficient to safely maintain a sufficient amount ofcompound in the bloodstream to affect anesthesia or sedation

In some embodiments, the compositions are used or administered at adosage so that a compound of formula (I) or a metabolite thereof (e.g.,wherein the ester has been hydrolyzed) is rapidly cleared, e.g. suchthat it has an in vivo concentration of less than 500 nM, less than 400nM, less than 300 nM, less than 250 nM, less than 200 nM, less than 150nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM,less than 10 nM, less than 5 nM, less than 1 nM, less than 0.5 nM, lessthan 0.1 nM, less than 0.05 nM, less than 0.01 nM, less than 0.005 nM,or less than 0.001 nM at and after a specific time following use oradministration, such as 15 min, 30 min, 1 hr, 1.5 hrs, 2 hrs, 2.5 hrs, 3hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs ormore of time after use or administration of the composition. In somecases, the specific time is less than 15 min, less than 10 min, orwithin 3-10 min after use or administration.

[In some embodiments, a compound of formula I is used or administered ata dosage so that it has an in vivo concentration of less than 500 nM at30 minutes after use or administration. In various embodiments, acompound of formula I is used or administered at a dosage so that itsinactive metabolite has an in vivo concentration of less than 500 nM at1 hr after use or administration. In some cases, the concentration isless than 100 nM and is achieved in 10 min or less after administrationor use of the compound as disclosed herein. In some cases, the compoundas disclosed herein has an in vivo concentration of less than 10 nM atless than 2 hours after use or administration, e.g., within 1-2 hoursafter administration.

The terms “administration of” and or “administering” a compound shouldbe understood to mean providing a compound or a composition describedherein to a subject in need of inducing anesthesia. As such, the term“administer” refers to the placement of a compound or compositiondescribed herein into a subject by a method or route which results in atleast partial localization of the compound or composition at a desiredsite such that general anesthesia or conscious sedation is inducedand/or maintained in the subject.

The compounds described herein can be administered by any appropriateroute known in the art including, but not limited to oral or parenteralroutes, including intravenous, intramuscular, subcutaneous, transdermal,airway (aerosol), pulmonary, nasal, rectal, and topical (includingbuccal and sublingual) administration.

In addition to those described above, exemplary modes of use andadministration include, but are not limited to, injection, infusion,instillation, inhalation, or ingestion. “Injection” includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intraventricular, intracapsular, intraorbital, intracardiac,intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, sub capsular, subarachnoid, intraspinal, intracerebrospinal, and intrasternal injection and infusion. In some embodiments,the compositions are administered by intravenous infusion or injection.

In some embodiments, the method includes use or administration of aninjection of a single effective dose of the compound which may or maynot be followed by a continuous infusion of the compound.

In some embodiments, the method includes use or administration of acontinuous infusion of an effective dose of the compound of formula (I)or a pharmaceutically composition comprising a compound of formula (I).

The compounds described herein can be used or administrated to a subjectin combination with another pharmaceutically active agent or treatmentmodality for a particular indication. Exemplary pharmaceutically activecompound include, but are not limited to, those found in Harrison'sPrinciples of Internal Medicine, 13^(th) Edition, Eds. T. R. Harrison etal. McGraw-Hill N.Y., NY; Physicians' Desk Reference, 50^(th) Edition,1997, Oradell N.J., Medical Economics Co.; Pharmacological Basis ofTherapeutics, 8^(th) Edition, Goodman and Gilman, 1990; United StatesPharmacopeia, The National Formulary, USP XII NF XVII, 1990; currentedition of Goodman and Oilman's The Pharmacological Basis ofTherapeutics; and current edition of The Merck Index, the completecontents of all of which are incorporated herein by reference.

Accordingly, in certain embodiments, the method also includes use oradministration to the subject an effective amount of a therapeutic agentselected from another sedative hypnotic agent, an analgesic agent, and aparalytic agent. Non-limiting examples of sedative hypnotic agentsinclude benzodiazepines, barbiturates, ketamine, propofol, isoflurane,and desflurane. Non-limiting examples of analgesic agents includenon-steroidal anti-inflammatory drugs (NSAIDs),paracetamol/acetaminophen, COX-2 inhibitors, and opioids. Non-limitingexamples of paralytic agents include rapacuronium, mivacurium,succinylcholine, vecuronium, and cisatracurium.

In some embodiments, a compound described herein is the only sedativehypnotic agent administered.

As used herein, a “subject” means a human or animal. Usually the animalis a vertebrate such as a primate, rodent, domestic animal or gameanimal. Primates include chimpanzees, cynomologous monkeys, spidermonkeys, and macaques, e.g., Rhesus. Rodents include mice, rats,woodchucks, ferrets, rabbits and hamsters. Domestic and game animalsinclude cows, horses, pigs, deer, bison, buffalo, feline species, e.g.,domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g.,chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.Patient or subject includes any subset of the foregoing, e.g., all ofthe above, but excluding one or more groups or species such as humans,primates or rodents. In certain embodiments of the aspects describedherein, the subject is a mammal, e.g., a primate, e.g., a human. Theterms, “patient” and “subject” are used interchangeably herein. Theterms, “patient” and “subject” are used interchangeably herein. Asubject can be male or female.

Preferably, the subject is a mammal. The mammal can be a human,non-human primate, mouse, rat, dog, cat, horse, or cow, but are notlimited to these examples. Mammals other than humans can beadvantageously used as subjects that represent animal models of humandiseases and disorders. In addition, compounds, compositions and methodsdescribed herein can be used to treat domesticated animals and/or pets.

The compounds according to the disclosure can be prepared by syntheticprocesses which are known to those skilled in the art, particularly inview of the state of the art and the specific preparatory examplesprovided below herein. Suitable modification to starting materials bymethods well known in the art may also be employed.

Synthesis of Compounds of Formula (I)

Further disclosed herein are methods of synthesizing a compound offormula (I). More specifically, provided herein is a method comprisinghydrolyzing ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate to obtain1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid; and reacting thecarboxylic acid with an alcohol of structureHOL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT.

Provided herein is yet another method of synthesizing a compound offormula (I). The method comprises coupling a compound of formula (II)and (a) a compound of formula (III) or (b) a compound of formula (IV):

wherein X is a carboxylic acid protecting group; removing X to form acarboxylic acid; coupling the carboxylic acid with an alcohol ofstructure HOL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT, wherein L², R⁷, R⁸, R⁹,R¹⁰, T and p are as defined for formula (I).

Protecting group X can be any protecting group known, including thosedescribed in Greene's Protective Groups in Organic Synthesis. Somespecific examples include O-alkyl and S-alkyl.

Specifically, synthesis of a compound of formula (I), when Z is N,comprises coupling a phenyl of formula (II):

, with an imidazole of formula (III):

wherein R², R³, R⁴, R⁵ and n are as defined above for formula (I) and Xis a protecting group; removing the protecting group on the carboxylic;and reacting the resulting carboxylic acid an alcohol having thestructure HO-L²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT, wherein L², R⁷, R⁸, R⁹,R¹⁰, T and p are as defined above for formula (I).

Synthesis of a compound of formula (I), when n is 0 and Z is N,comprises hydrolyzing the ester ethyl group from R- or S-etomidate andreacting the resulting carboxylic acid then reacted with the desiredalcohol.

Synthesis of a compound of formula (I), when Z is CR⁶, comprises can becoupling a phenyl of formula (II) described above with a pyrrole offormula (IV):

wherein R⁴, R⁵, and R⁶ are as defined above for formula (I) and X iscarboxylic acid protecting group; removing the protecting group on thecarboxylic; and reacting the resulting carboxylic acid reacted with analcohol having the structure HO-L²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT,wherein L², R⁷, R⁸, R⁹, R¹⁰, T and p are as defined above for formula(I).

The reaction between phenyl of formula (II) and imidazole of formula(III) or pyrrole of formula (IV) proceeds with inversion ofconfiguration. Thus, using a phenyl of appropriate configuration, thecompound of formula (I) with the correct configuration at the carbon towhich the R² substituent is attached can be obtained. For example, usinga phenyl with the S configuration leads to a compound of formula (I)having the R configuration. The phenyls of formula (II) are easilyprepared by reduction of phenyl alkyl ketones and derivatives thereof.

Some Definitions

Unless stated otherwise, or implicit from context, the following termsand phrases include the meanings provided below. Unless explicitlystated otherwise, or apparent from context, the terms and phrases belowdo not exclude the meaning that the term or phrase has acquired in theart to which it pertains. The definitions are provided to aid indescribing particular embodiments, and are not intended to limit theclaimed invention, because the scope of the invention is limited only bythe claims. Further, unless otherwise required by context, singularterms shall include pluralities and plural terms shall include thesingular.

As used herein the term “comprising” or “comprises” is used in referenceto compositions, methods, and respective component(s) thereof, that areessential to the invention, yet open to the inclusion of unspecifiedelements, whether essential or not.

The singular terms “a,” “an,” and “the” include plural referents unlesscontext clearly indicates otherwise. Similarly, the word “or” isintended to include “and” unless the context clearly indicatesotherwise.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of this disclosure,suitable methods and materials are described below. The term “comprises”means “includes.” The abbreviation, “e.g.” is derived from the Latinexempli gratia, and is used herein to indicate a non-limiting example.Thus, the abbreviation “e.g.” is synonymous with the term “for example.”

The terms “decrease”, “reduced”, “reduction”, “decrease” or “inhibit”are all used herein generally to mean a decrease by a statisticallysignificant amount. However, for avoidance of doubt, ““reduced”,“reduction” or “decrease” or “inhibit” means a decrease by at least 10%as compared to a reference level, for example a decrease by at leastabout 20%, or at least about 30%, or at least about 40%, or at leastabout 50%, or at least about 60%, or at least about 70%, or at leastabout 80%, or at least about 90% or up to and including a 100% decrease(e.g. absent level as compared to a reference sample), or any decreasebetween 10-100% as compared to a reference level.

The terms “increased”, “increase” or “enhance” or “activate” are allused herein to generally mean an increase by a statically significantamount; for the avoidance of any doubt, the terms “increased”,“increase” or “enhance” or “activate” means an increase of at least 10%as compared to a reference level, for example an increase of at leastabout 20%, or at least about 30%, or at least about 40%, or at leastabout 50%, or at least about 60%, or at least about 70%, or at leastabout 80%, or at least about 90% or up to and including a 100% increaseor any increase between 10-100% as compared to a reference level, or atleast about a 2-fold, or at least about a 3-fold, or at least about a4-fold, or at least about a 5-fold or at least about a 10-fold increase,or any increase between 2-fold and 10-fold or greater as compared to areference level.

The term “statistically significant” or “significantly” refers tostatistical significance and generally means at least two standarddeviations (2SD) away from a reference level. The term refers tostatistical evidence that there is a difference. It is defined as theprobability of making a decision to reject the null hypothesis when thenull hypothesis is actually true.

As used herein, the term “alkyl” refers to saturated straight-chain,branched-chain or cyclic hydrocarbon radicals. Examples of alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, cyclopropyl-, n-butyl, tert-butyl, neopentyl, n-hexyl,cyclohexyl, n-octyl, n-decyl, n-dodecyl and n-hexadecyl radicals.Backbone of the alkyl can be optionally inserted with one or moreheteroatoms, such as N, O, or S. The term “alkylene” refers to divalentalkyl.

As used herein, the term “alkenyl” refers to unsaturated straight-chain,branched-chain or cyclic hydrocarbon radicals having at least onecarbon-carbon double bond. Examples of alkenyl radicals include, but arenot limited to, allyl, butenyl, hexenyl and cyclohexenyl radicals.Backbone of the alkenyl can be optionally inserted with one or moreheteroatoms, such as N, O, or S. The term “alkenylene” refers todivalent alkenyl.

As used herein, the term “alkynyl” refers to unsaturated hydrocarbonradicals having at least one carbon-carbon triple bond. Representativealkynyl groups include, but are not limited to, ethynyl, 1-propynyl,1-butynyl, isopentynyl, 1,3-hexa-diyn-yl, n-hexynyl, 3-pentynyl,1-hexen-3-ynyl and the like. Backbone of the alkynyl can be optionallyinserted with one or more heteroatoms, such as N, O, or S. The term“alkynylene” refers to divalent alkynyl.

As used herein, the term “halogen” refers to an atom selected fromfluorine, chlorine, bromine and iodine. The term “halogen radioisotope”refers to a radionuclide of an atom selected from fluorine, chlorine,bromine and iodine.

The term “aryl” refers to monocyclic, bicyclic, or tricyclic aromaticring system wherein 0, 1, 2, 3, or 4 atoms of each ring may besubstituted by a substituent. Exemplary aryl groups include, but are notlimited to, benzyl, phenyl, naphthyl, anthracenyl, azulenyl, fluorenyl,indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.

The term “cyclyl” or “cycloalkyl” refers to saturated and partiallyunsaturated cyclic hydrocarbon groups having 3 to 12 carbons, forexample, 3 to 8 carbons, and, for example, 3 to 6 carbons, wherein thecycloalkyl group additionally may be optionally substituted. Exemplarycycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cyclooctyl, and the like.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent. Exemplaryheteroaryl groups include, but are not limited to, pyridyl, furyl orfuranyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl,pyridazinyl, pyrazinyl, quinolinyl, indolyl, thiazolyl, naphthyridinyl,and the like.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Exemplaryheterocyclyl groups include, but are not limited to piperazinyl,pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

As used herein, the term “substituted” refers to independent replacementof one or more (typically 1-4) of the hydrogen atoms on the substitutedmoiety with substituents independently selected from the group ofsubstituents listed below in the definition for “substituents” orotherwise specified. Suitable substituents include, without limitation,acyl, acylamino, acyloxy, alkanesulfonamido, alkanesulfonyl, alkaryl,alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylcarbanoyl,alkynyl, amido, amino, aminoalkyl, aralkyl, aralkylsulfonamido,arenesulfonamido, arenesulfonyl, aryl, arylamino, arylcarbanoyl,aryloxy, carbonyl, carboxy, cyano, haloalkyl, halogen, heteroaryl,heterocycloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, andureido groups. In some cases, two substituents, together with thecarbons to which they are attached to can form a ring.

The term “derivative” as used herein refers to a chemical substancerelated structurally to another, i.e., an “original” substance, whichcan be referred to as a “parent” compound. A “derivative” can be madefrom the structurally-related parent compound in one or more steps. Insome embodiments, the general physical and chemical properties of aderivative can be similar to or different from the parent compound.

As used herein, the term “PEG” means an ethylene glycol polymer thatcontains about 20 to about 2000000 linked monomers, typically about50-1000 linked monomers, usually about 100-300. Polyethylene glycolsinclude PEGs containing various numbers of linked monomers, e.g., PEG20,PEG30, PEG40, PEG60, PEG80, PEG100, PEG115, PEG200, PEG 300, PEG400,PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600,PEG5000, PEG6000, PEG8000, PEG11000, PEG12000, PEG2000000 and anymixtures thereof.

As used here in the term “isomer” refers to compounds having the samemolecular formula but differing in structure. Isomers which differ onlyin configuration and/or conformation are referred to as “stereoisomers.”The term “isomer” is also used to refer to an enantiomer.

The term “enantiomer” is used to describe one of a pair of molecularisomers which are mirror images of each other and non-superimposable.Other terms used to designate or refer to enantiomers include“stereoisomers” (because of the different arrangement or stereochemistryaround the chiral center; although all enantiomers are stereoisomers,not all stereoisomers are enantiomers) or “optical isomers” (because ofthe optical activity of pure enantiomers, which is the ability ofdifferent pure enantiomers to rotate planepolarized light in differentdirections). Enantiomers generally have identical physical properties,such as melting points and boiling points, and also have identicalspectroscopic properties. Enantiomers can differ from each other withrespect to their interaction with plane-polarized light and with respectto biological activity.

The designations “R” and “S” are used to denote the absoluteconfiguration of the molecule about its chiral center(s). Thedesignations may appear as a prefix or as a suffix; they may or may notbe separated from the isomer by a hyphen; they may or may not behyphenated; and they may or may not be surrounded by parentheses.

The designations or prefixes “(+)” and “(−)” are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)meaning that the compound is levorotatory (rotates to the left). Acompound prefixed with (+) is dextrorotatory (rotates to the right).

The term “racemic mixture,” “racemic compound” or “racemate” refers to amixture of the two enantiomers of one compound. An ideal racemic mixtureis one wherein there is a 50:50 mixture of both enantiomers of acompound such that the optical rotation of the (+) enantiomer cancelsout the optical rotation of the (−) enantiomer.

The term “resolving” or “resolution” when used in reference to a racemicmixture refers to the separation of a racemate into its twoenantiomorphic forms (i.e., (+) and (−); 65 (R) and (S) forms). Theterms can also refer to enantioselective conversion of one isomer of aracemate to a product.

The term “enantiomeric excess” or “ee” refers to a reaction productwherein one enantiomer is produced in excess of the other, and isdefined for a mixture of (+)- and (−)-enantiomers, with compositiongiven as the mole or weight or volume fraction F(+) and F(−) (where thesum of F(+) and F(−)=1). The enantiomeric excess is defined as *F(+)−F(−)* and the percent enantiomeric excess by 100x*F(+)−F(−)*. The“purity” of an enantiomer is described by its ee or percent ee value (%ee).

Whether expressed as a “purified enantiomer” or a “pure enantiomer” or a“resolved enantiomer” or “a compound in enantiomeric excess”, the termsare meant to indicate that the amount of one enantiomer exceeds theamount of the other. Thus, when referring to an enantiomer preparation,both (or either) of the percent of the major enantiomer (e.g. by mole orby weight or by volume) and (or) the percent enantiomeric excess of themajor enantiomer may be used to determine whether the preparationrepresents a purified enantiomer preparation.

The term “enantiomeric purity” or “enantiomer purity” of an isomerrefers to a qualitative or quantitative measure of the purifiedenantiomer; typically, the measurement is expressed on the basis of eeor enantiomeric excess.

The terms “substantially purified enantiomer,” “substantially resolvedenantiomer” “substantially purified enantiomer preparation” are meant toindicate a preparation (e.g. derived from non-optically active startingmaterial, substrate, or intermediate) wherein one enantiomer has beenenriched over the other, and more preferably, wherein the otherenantiomer represents less than 20%, more preferably less than 10%, andmore preferably less than 5%, and still more preferably, less than 2% ofthe enantiomer or enantiomer preparation.

The terms “purified enantiomer,” “resolved enantiomer” and “purifiedenantiomer preparation” are meant to indicate a preparation (e.g.derived from non-optically active starting material, substrates orintermediates) wherein one enantiomer (for example, the R-enantiomer) isenriched over the other, and more preferably, wherein the otherenantiomer (for example the S-enantiomer) represents less than 30%,preferably less than 20%, more preferably less than 10% (e.g. in thisparticular instance, the R-enantiomer is substantially free of theS-enantiomer), and more preferably less than 5% and still morepreferably, less than 2% of the preparation. A purified enantiomer maybe synthesized substantially free of the other enantiomer, or a purifiedenantiomer may be synthesized in a stereo-preferred procedure, followedby separation steps, or a purified enantiomer may be derived from aracemic mixture.

The term “enantioselectivity,” also called the enantiomeric ratioindicated by the symbol “E,” refers to the selective capacity of anenzyme to generate from a racemic substrate one enantiomer relative tothe other in a product racemic mixture; in other words, it is a measureof the ability of the enzyme to distinguish between enantiomers. Anonselective reaction has an E of 1, while resolutions with E's above 20are generally considered useful for synthesis or resolution. Theenantioselectivity resides in a difference in conversion rates betweenthe enantiomers in question. Reaction products are obtained that areenriched in one of the enantiomers; conversely, remaining substrates areenriched in the other enantiomer. For practical purposes it is generallydesirable for one of the enantiomers to be obtained in large excess.This is achieved by terminating the conversion process at a certaindegree of conversion.

The term “RT” refers to room temperature, about 20° C. to 25° C.

In jurisdictions that forbid the patenting of methods that are practicedon the human body, the meaning of “administering” of a composition to ahuman subject shall be restricted to prescribing a controlled substancethat a human subject will self-administer by any technique (e.g.,orally, inhalation, topical application, injection, insertion, etc.).The broadest reasonable interpretation that is consistent with laws orregulations defining patentable subject matter is intended. Injurisdictions that do not forbid the patenting of methods that arepracticed on the human body, the “administering” of compositionsincludes both methods practiced on the human body and also the foregoingactivities.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

Aspect disclosed herein can be illustrated by any of the followingnumbered paragraphs:

-   1. A compound according to formula (I)

-   -   wherein,    -   R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT;    -   R² is R¹, optionally substituted linear or branched C₁-C₁₀        alkyl, optionally substituted linear or branched C₂-C₁₀ alkenyl,        or optionally substituted linear or branched C₂-C₁₀ alkynyl,        wherein the backbone of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀        alkynyl optionally comprises one or more heteroatoms;    -   each R₃ is independently halogen, CN, CF₃, SR², SOR², SO₂R²,        OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   Z is N or CR⁶;    -   R⁴, R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃,        SR², SOR², SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   R⁷ and R⁸ are independently hydrogen, optionally substituted        linear or branched C₁-C₁₀ alkyl, optionally substituted linear        or branched C₂-C₁₀ alkenyl, optionally substituted linear or        branched C₂-C₁₀ alkynyl, or R⁷ and R⁸ together with the carbon        they are attached to form an optionally substituted 3-8 membered        cyclyl or heterocyclyl;    -   R⁹ and R¹⁰ are independently hydrogen, optionally substituted        linear or branched C₁-C₁₀ alkyl, optionally substituted linear        or branched C₂-C₁₀ alkenyl, optionally substituted linear or        branched C₂-C₁₀ alkynyl, optionally substituted C₄-C₈ cyclyl,        optionally substituted C₃-C₈ heterocyclyl, or R⁹ and R¹⁰        together with the carbon they are attached to form an optionally        substituted 3-8 membered cyclyl or heterocyclyl, or    -   R⁷ and R⁹ together with the carbons they are attached to form an        optionally substituted 3-8 membered cyclyl, heterocyclyl, aryl        or heteroaryl;    -   L¹ and L² are independently a bond, optionally substituted        linear or branched C₁-C₁₀ alkylene, optionally substituted        linear or branched C₂-C₁₀ alkenylene, or optionally substituted        linear or branched C₂-C₁₀ alkynylene, wherein the backbone of        C₁-C₁₀ alkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀ alkynylene        optionally comprises one or more heteroatoms;    -   T is H, a linear or branched, substituted or unsubstituted        C₁-C₁₀ alkyl, linear or branched, substituted or unsubstituted        C₂-C₁₀ alkenyl, linear or branched, substituted or unsubstituted        C₂-C₁₀ alkynyl, optionally substituted cyclyl, optionally        substituted heterocylcyl, optionally substituted aryl,        optionally substituted heteroaryl, or PEG, wherein the backbone        of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl optionally        comprises one or more heteroatoms;    -   n is an integer from 0-5; and    -   p is 0 or 1, provided that at least one of R⁷, R⁸, R⁹ and R¹⁰ is        not hydrogen,    -   or a salt, solvate, or ester thereof.

-   2. The compound of paragraph 1, having a structure of formula (IA),    (IB) or (IC):

-   3. The compound of paragraph 1 or 2, wherein n is 0 or 1.-   4. The compound of any of paragraphs 1-3, wherein p is 0 or 1.-   5. The compound of any of paragraphs 1-4, wherein L¹ is a bond,    optionally substituted linear or branched C₁-C₁₀alkylene, optionally    substituted linear or branched C₂-C₁₀alkenylene, or optionally    substituted linear or branched C₂-C₁₀alkynylene; wherein the    backbone of C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene    optionally comprises one or more heteroatoms.-   6. The compound of any of paragraphs 1-5, wherein L² is a bond,    optionally substituted linear or branched C₁-C₁₀alkylene, optionally    substituted linear or branched C₂-C₁₀alkenylene, or optionally    substituted linear or branched C₂-C₁₀alkynylene; wherein the    backbone of C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene    optionally comprises one or more heteroatoms.-   7. The compound of any of paragraphs 1-6, wherein T is hydrogen,    optionally substituted C₁-C₁₀alkyl, or optionally substituted cyclyl    or heterocyclyl.-   8. The compound of paragraph 7, wherein T is selected from the group    consisting of methyl, ethyl, propyl, isopropyl, butyl, t-butyl,    pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl,    2,3-dimethylbutyl, 2,2-dimethylbutyl, 2-hydroxylpropyl, cyclopropyl,    cyclobutyl, oxetanyl, morpholinyl, and oxazolindinyl.-   9. The compound of any of paragraphs 1-8, wherein Z is N.-   10. The compound of any of paragraphs 1-8, wherein Z is CR⁶.-   11. The compound of paragraph 10, wherein at least one of R⁴ and R⁶    is Br or CN.-   12. The compound of paragraph 10 or 11, wherein R⁶ is hydrogen.-   13. The compound of any of paragraphs 1-12, wherein R⁴ is hydrogen.-   14. The compound of any of paragraphs 1-13, wherein R⁵ is hydrogen.-   15. The compound of any of paragraphs 1-14, wherein R² is optionally    substituted C₁-C₁₀ alkyl.-   16. The compound of paragraph 15, wherein R² is selected from the    group consisting of methyl, ethyl, propyl, isopropyl, butyl,    t-butyl, pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl,    2,3-dimethylbutyl, and 2,2-dimethylbutyl.-   17. The compound of any of paragraphs 1-16, wherein the carbon to    which R² is attached to has the R configuration.-   18. The compound of any of paragraphs 1-17, wherein R⁹ and R¹⁰ are    independently hydrogen, optionally substituted C₁-C₁₀alkyl,    optionally substituted C₄-C₆cyclyl or optionally substituted    C₄-C₆heterocyclyl; or R⁹ and R¹⁰ together with the carbon they are    attached to form a 3-, 4-, 5, or 6-membered cyclyl.-   19. The compound any of paragraphs 1-18, wherein R⁹ and R¹⁰ are    independently optionally substituted C₁-C₁₀alkyl.-   20. The compound of any of paragraphs 1-19, wherein R⁹ and R¹⁰ are    the same.-   21. The compound of any of paragraphs 1-18, wherein one of R⁹ and    R¹⁰ is optionally substituted C₁-C₁₀alkyl, optionally substituted    C₄-C₆cyclyl or optionally substituted C₄-C₆heterocyclyl, and the    other is hydrogen.-   22. The compound of any of paragraphs 1-21, wherein R⁹ and R¹⁰ are    independently selected from the group consisting of hydrogen,    methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl,    hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl,    2,2-dimethylbutyl, phenyl, pyridyl, thiophene, furanyl, pyrazolyl,    cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and    piperdinyl.-   23. The compound of any of paragraphs 1-19, 21 or 22, wherein the    carbon to which R⁹ and R¹⁰ are attached has the R configuration.-   24. The compound of any of paragraphs 1-19, 21 or 22, wherein the    carbon to which R⁹ and R¹⁰ are attached has the S configuration.-   25. The compound of any of paragraphs 1-24, wherein R⁷ and R⁸ are    independently hydrogen, optionally substituted C₁-C₁₀alkyl,    optionally substituted C₄-C₆cyclyl or optionally substituted    C₄-C₆heterocyclyl; or R⁷ and R⁸ together with the carbon they are    attached to form a 3-, 4-, 5, or 6-membered cyclyl.-   26. The compound of any of paragraphs 1-25, wherein R⁷ and R⁸ are    independently optionally substituted C₁-C₁₀alkyl.-   27. The compound of any of paragraphs 1-26, wherein R⁷ and R⁸ are    the same.-   28. The compound of any of paragraphs 1-25, wherein one of R⁷ and R⁸    is optionally substituted C₁-C₁₀alkyl, optionally substituted    C₄-C₆cyclyl or optionally substituted C₄-C₆heterocyclyl, and the    other is hydrogen.-   29. The compound of any of paragraphs 1-28, wherein R⁷ and R⁸ are    independently selected from the group consisting of hydrogen,    methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl,    hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl,    2,2-dimethylbutyl, phenyl, pyridyl, thiophene, furanyl, pyrazolyl,    cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and    piperdinyl.-   30. The compound of any of paragraphs 1-27, 28 or 29, wherein the    carbon to which R⁷ and R⁸ are attached has the R configuration.-   31. The compound of any of paragraphs 1-27, 28 or 29, wherein the    carbon to which R⁷ and R⁸ are attached has the S configuration.-   32. The compound of any of paragraphs 1-31, wherein R⁷ and R⁹    together with the carbons they are attached to form an optionally    substituted 3-8 membered cyclyl or heterocyclyl.-   33. A compound according to formula (I)

-   -   wherein,    -   R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT;    -   R² is R¹ or a linear or branched, substituted or unsubstituted        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl, wherein        backbone of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl can        contain one or more heteroatoms;    -   each R₃ is independently halogen, CN, CF₃, SR², SOR², SO₂R²,        OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   Z is N or CR⁵;    -   R⁴, R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃,        SR², SOR², SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, linear or        branched, substituted or unsubstituted C₁-C₁₀ alkyl, linear or        branched, substituted or unsubstituted C₂-C₁₀ alkenyl, linear or        branched, substituted or unsubstituted C₂-C₁₀ alkynyl, or R⁷ and        R⁸ together with the carbon they are attached to form a 3-8        membered cyclyl or heterocyclyl, or R⁹ and R¹⁰ together with the        carbon they are attached to form a 3-8 membered cyclyl or        heterocyclyl, provided that at least one of R⁷, R⁸, R⁹ and R¹⁰        is not hydrogen, and wherein the backbone of the C₁-C₂₀        alkylene, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl can        contain one or more heteroatoms;    -   L¹ and L² are independently a bond, a substituted or        unsubstituted C₁-C₁₀ alkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀        alkynylene, wherein backbone of alkylene can contain one or more        heteroatoms;    -   T is H, a linear or branched, substituted or unsubstituted        C₁-C₁₀ alkyl, linear or branched, substituted or unsubstituted        C₂-C₁₀ alkenyl, linear or branched, substituted or unsubstituted        C₂-C₁₀ alkynyl, optionally substituted cyclyl, optionally        substituted heterocylcyl, optionally substituted aryl,        optionally substituted heteroaryl, or PEG, wherein the backbone        of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl can contain one        or more heteroatoms;    -   n is an integer from 0-5; and    -   p is 0 or 1.

-   34. The compound of paragraph 33, wherein said compound is present    in the form of a pure enantiomer.

-   35. The compound of any of paragraphs 33-34, wherein the carbon to    which R² is attached has the R configuration.

-   36. The compound of any of paragraphs 33-35, wherein R² is selected    from the group consisting of methyl, ethyl, propyl, isopropyl,    butyl, t-butyl, pentyl, neopentyl, hexyl, 2-methylpentyl,    3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl.

-   37. The compound of any of paragraphs 33-36, wherein T is selected    from the group consisting of hydrogen, methyl, ethyl, propyl,    isopropyl, butyl, t-butyl, pentyl, neopentyl, hexyl, 2-methylpentyl,    3-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, and    2-hydroxylpropyl.

-   38. The compound of any of paragraphs 33-37, wherein n is 0 or 1.

-   39. The compound of any of paragraphs 33-38, wherein L¹ is a bond.

-   40. The compound of any of paragraphs 33-39, wherein L² is a bond.

-   41. The compound of any of paragraphs 33-40, wherein one of R⁹ or    R¹⁰ is C₁-C₁₀ alkyl and the other is hydrogen.

-   42. The compound of any of paragraphs 33-40, wherein both of R⁹ and    R¹⁰ are independently C₁-C₁₀ alkyl.

-   43. The compound of paragraph 41 or 42, wherein the carbon to which    R⁹ and R¹⁰ are attached has the R configuration.

-   44. The compound of paragraph 41 or 42, wherein the carbon to which    R⁹ and R¹⁰ are attached has the S configuration.

-   45. The compound of any of paragraphs 41-44, wherein R⁹ and R¹⁰ are    selected from the group consisting of hydrogen, methyl, ethyl,    propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl, hexyl,    2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl    and any combinations thereof.

-   46. The compound of any of paragraphs 42-45, wherein R⁹ and R¹⁰ are    both same or together with the carbon they are attached to form a 3    membered ring.

-   47. The compound of any of paragraphs 33-46, wherein p is 0.

-   48. The compound of any of paragraphs 33-46, wherein one of R⁷ and    R⁸ is C₁-C₁₀ alkyl and the other is hydrogen.

-   49. The compound of any of paragraphs 33-46, wherein both of R⁷ and    R⁸ are independently C₁-C₁₀ alkyl.

-   50. The compound of paragraph 48 or 49, wherein the carbon to which    R⁷ and R⁸ are attached has the R configuration.

-   51. The compound of paragraph 48 or 49, wherein the carbon to which    R⁷ and R⁸ are attached has the S configuration.

-   52. The compound of any of paragraphs 48-51, wherein R⁷ and R⁸ are    selected from the group consisting of hydrogen, methyl, ethyl,    propyl, isopropyl, butyl, t-butyl, pentyl, neopentyl, hexyl,    2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl    and any combinations thereof.

-   53. The compound of any of paragraphs 48-52, wherein R⁷ and R⁷ are    both the same or together with the carbon they are attached to form    a 3 membered ring.

-   54. The compound of any of paragraphs 33-53, wherein R⁵ is hydrogen.

-   55. The compound of any of paragraphs 33-54, wherein at least one of    R⁴ and R⁶ is hydrogen.

-   56. The compound of any of paragraphs 33-55, wherein at least one of    R⁴ and R⁶ is Br or CN.

-   57. The compound of paragraph 56, wherein R⁴ is H and R⁶ is Br or    CN.

-   58. The compound of paragraph 56, wherein R⁴ is Br or CN.

-   59. A compound having a structure of formula (I):

wherein

-   -   R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT;    -   R² is R¹ or a linear or branched, substituted or unsubstituted        C₁-C₁₀alkyl, C₂-C₁₀alkenyl, or C₂-C₁₀alkynyl, wherein the        backbone of C₁-C₁₀alkyl, C₂-C₁₀alkenyl, or C₂-C₁₀alkynyl        optionally comprises one or more heteroatoms;    -   each R³ is independently halogen, CN, CF₃, SR², SOR², SO₂R²,        OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   Z is N or CR⁶;    -   R⁴, R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃,        SR², SOR², SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²;    -   R⁷ and R⁸ are independently hydrogen, linear or branched,        substituted or unsubstituted C₁-C₁₀alkyl, C₂-C₁₀alkenyl, or        C₂-C₁₀alkynyl, or R⁷ and R⁸ taken together form an optionally        substituted 3-8 membered carbocyclyl or heterocyclyl;    -   R⁹ and R¹⁰ are independently hydrogen, optionally substituted        C₄-C₈ cyclyl or optionally substituted C₃-C₈heterocyclyl, with        the proviso that at least one of R⁹, and R¹⁰ is not hydrogen;    -   or R⁷ and R⁹ taken together form an optionally substituted 3-8        membered carbocyclyl, heterocyclyl, aryl, or heteroaryl;    -   L¹ and L² are independently a bond, a linear or branched,        substituted or unsubstituted C₁-C₁₀alkylene, C₂-C₁₀alkenylene,        or C₂-C₁₀alkynylene; wherein the backbone of C₁-C₁₀alkylene,        C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene optionally comprises one        or more heteroatoms;    -   T is hydrogen, linear or branched, substituted or unsubstituted        C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, optionally        substituted cyclyl, optionally substituted heterocyclyl,        optionally substituted aryl, optionally substituted heteroaryl,        or PEG, wherein the backbone of C₁-C₁₀alkyl, C₂-C₁₀alkenyl, or        C₂-C₁₀alkynyl optionally comprises one or more heteroatoms;    -   each n is an integer of 0-5; and    -   each p is 0 or 1,

or a salt, solvate, or ester thereof.

-   60. The compound of paragraph 59, wherein L¹ is a linear or    branched, substituted or unsubstituted C₁-C₁₀alkylene,    C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; wherein the backbone of    C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene optionally    comprises one or more heteroatoms.-   61. The compound of paragraph 59 or 60, wherein L² is a linear or    branched, substituted or unsubstituted C₁-C₁₀alkylene,    C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; wherein the backbone of    C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene optionally    comprises one or more heteroatoms.-   62. The compound of paragraph 59 or 61 having a structure of formula    (IA):

-   63. The compound of paragraph 59 having a structure of formula (TB):

-   64. The compound of paragraph 59 having a structure of formula (IC):

-   65. The compound of any one of paragraphs 59 to 64, wherein Z is N.-   66. The compound of any one of paragraphs 59 to 64, wherein Z is    CR⁶.-   67. The compound of paragraph 66, wherein R⁶ is H.-   68. The compound of any one of paragraphs 59 to 67, wherein R⁹ is    optionally substituted C₄-C₆cyclyl and R¹⁰ is hydrogen.-   69. The compound of any one of paragraphs 59 to 67, wherein R⁹ is    optionally substituted C₄-C₆heterocyclyl and R¹⁰ is hydrogen.-   70. The compound of any one of paragraphs 59 to 69, wherein R⁷ and    R⁹ together form an optionally substituted 3-8 membered cyclyl or    heterocyclyl.-   71. The compound of any one of paragraphs 59 to 70, wherein R⁴ is    hydrogen.-   72. The compound of any one of paragraphs 59 to 71, wherein R⁵ is    hydrogen.-   73. The compound of any one of paragraphs 59 to 72, wherein n is 0.-   74. The compound of any one of paragraphs 59 to 72, wherein n is 1.-   75. The compound of any one of paragraphs 59 to 74, wherein R² is    optionally substituted C₁-C₁₀ alkyl.-   76. The compound of paragraph 75, wherein R² is methyl, ethyl,    n-propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl,    pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl,    2,3-dimethylbutyl, or 2,2-dimethylbutyl.-   77. The compound of any one of paragraphs 59 to 76, wherein the    carbon to which R² is attached is in the R configuration.-   78. The compound of any one of paragraphs 59 to 77, wherein T is    optionally substituted C₁-C₁₀alkyl.-   79. The compound of paragraph 78, wherein T is methyl or ethyl.-   80. The compound of any one of paragraphs 59 to 77, wherein T is    optionally substituted cyclyl or heterocyclyl.-   81. The compound of paragraph 80, wherein T is cyclopropyl,    cyclobutyl, oxetanyl, morpholinyl, or oxazolindinyl.-   82. The compound of any of paragraphs 1-32, wherein the compound is    in the form of a single diastereomer-   83. The compound of any of paragraphs 1-33, wherein the compound is    in the form of a single enantiomer.-   84. The compound of any of paragraphs 1-34, wherein the compound is    in the form of a salt.-   85. The compound of any of paragraphs 1-34, wherein the compound is    in the form of a solvate.-   86. The compound of paragraph 1, wherein the compound of formula (I)    is selected from the group consisting of

-   87. The compound of paragraph 1, wherein the compound of formula (I)    is selected from the group consisting of

-   88. A compound having a structure selected from the group consisting    of

or a salt, solvate, or ester thereof.

-   89. A pharmaceutical composition comprising a compound of any of    paragraphs 1-88 and a pharmaceutically acceptable carrier.-   90. A method for providing anesthesia or sedation to a subject    comprising administering to the subject a therapeutically effective    amount of a compound of paragraphs 1-89 or a pharmaceutical    composition of paragraph 89.-   91. The compound of any of paragraphs 1-88 for use as an anesthetic    or sedative.-   92. Use of a compound of any of paragraphs 1-88 in the preparation    of a medicament for use as an anesthetic or sedative.-   93. Use of a compound of any of paragraphs 1-88 as an anesthetic or    sedative.-   94. The method, compound or use of any of paragraphs 90-93, wherein    the subject is a mammal.-   95. The method, compound or use of any of paragraphs 91-93, wherein    the subject is a human.-   96. A method of preparing a compound of paragraph 1, 33, or 59,    comprising:    -   (i) hydrolyzing        ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate to obtain        1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid; and    -   (ii) reacting the carboxylic acid with an alcohol of structure        HO-L²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT, wherein L², R⁷, R⁸, R⁹,        R¹⁰, T and p are as defined for formula (I).-   97. A method of preparing a compound of paragraph 1, 33, or 59,    comprising:    -   (i) coupling a compound of formula (II), and (a) a compound of        formula (III) or (b) a compound of formula (IV):

-   -    wherein R², R³, R⁴, R⁵, R⁶, and n are as defined for        formula (I) and X is carboxylic acid protecting group;    -   (ii) removing the protecting group X to form a carboxylic acid;        and    -   (iii) coupling the carboxylic acid with an alcohol of structure        HO-L²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT, wherein L², R⁷, R⁸, R⁹,        R¹⁰, T and p are as defined for formula

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

One skilled in the art would also readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent herein. Themolecular complexes and the methods, procedures, treatments, molecules,specific compounds described herein are presently representative ofpreferred embodiments, are exemplary, and are not intended aslimitations on the scope of the invention. Changes therein and otheruses will occur to those skilled in the art which are encompassed withinthe spirit of the invention are defined by the scope of the claims.

EXAMPLES

The disclosure is further illustrated by the following examples whichshould not be construed as limiting. The examples are illustrative only,and are not intended to limit, in any manner, any of the aspectsdescribed herein.

Example 1 Materials and Methods

Animals:

All studies were conducted in accordance with rules and regulations ofthe Subcommittee on Research Animal Care at the Massachusetts GeneralHospital, Boston, Mass. Adult male Sprague-Dawley rats (230-350 gm) werepurchased from Charles River Laboratories (Wilmington, Mass.) and housedin the Massachusetts General Hospital Center for Comparative Medicineanimal care facility. All drugs were administered through a femoralvenous catheter pre-implanted by the vendor prior to animal delivery toour animal care facility.

Hypnotic Drugs:

Etomidate was purchased from Bachem (Torrance, Calif.). Etomidate esterswere synthesized (>99% purity) either within our laboratory or byAberjona Laboratories (Beverly, Mass.) using the following previouslydescribed general procedure.¹²

Step 1: Synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylicacid

(R)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate.HCl((R)-etomidate.HCl) in methanol and 10% aqueous NaOH was refluxed for 30min. After cooling, the solution was neutralized with 12 M HCl. Themixture was dried by rotary evaporation, the residue suspended inmethanol-dichloromethane 1:4 v/v, and the sodium chloride removed byfiltration. (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 1 wasobtained by chromatography on a silica gel column equilibrated withmethanol-dichloromethane 1:4 V/V.

Step 2: Synthesis of Etomidate Ester (FIG. 2)

Dicyclohexylcarbodiimide and p-dimethylaminopyridine were added to amixture composed of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic andthe desired alcohol (in equimolar ratios) in anhydrous dichloromethane(FIG. 2). These alcohols were either purchased commercially orsynthesized essentially as described by Bartlett and Rylander. Thesolution was stirred at room temperature for 48 h. The precipitate wasremoved by filtration and the clear solution applied to a silica gelcolumn equilibrated with dichloromethane. Elution with 10% ether indichloromethane gave the product, which was further purified bypreparative thin layer chromatography with hexane-ethyl acetate 1:1 v/von 1 mm thick silica gel plate. The identity of the product wasconfirmed by nuclear magnetic resonance spectroscopy.

The inventors used a nomenclature system for these new compounds thatwas based upon four criteria (FIG. 3). First, the length of the carbonchain linking the labile ester to the etomidate backbone. Etomidateanalogs have two methylene groups in this chain whereas metomidateanalogs have only one. Second, the identity of the aliphatic group orgroups (i.e. methyl, dimethyl, isopropyl, or cyclopropyl). Third, thespecific location of the aliphatic group on the carbon chain (foretomidate esters with carbon linkers composed of two methylene groups).The carbon immediately adjacent to the metabolically-labile ester wasdefined as the a carbon whereas the more distant one was the 13 carbon.Finally, the enantiomeric configuration of the new chiral center (R orS) that results from the addition of the new aliphatic group.

Measurement of In Vivo Hypnotic Potency and Duration of Action:

The hypnotic potencies of etomidate, metomidate, and etomidate esterswere assessed in rats using a loss of righting reflexes (LORR) assay.¹²Briefly, the desired dose of hypnotic in dimethyl sulfoxide or salinevehicle was rapidly injected through the femoral venous catheterfollowed by a 1-ml normal saline flush. Immediately after injection,rats were turned supine. A rat was judged to have LORR if it failed toright itself (onto all four paws) after drug administration. A stopwatchwas used to measure the duration of LORR, which was defined as the timefrom drug injection until the animal spontaneously righted itself. Foreach etomidate ester, the ED₅₀ for LORR was determined from a data setpossessing at least 15 doses using the method of Waud.²⁰

In Vitro Metabolic Half-Life of Hypnotics in Rat Blood:

On the day of study, whole blood was drawn from the femoral venouscatheters of 3 Sprague-Dawley rats (1-2 ml/rat), immediatelyanticoagulated with heparin (38 U), pooled, and stored on ice. A 1 mlaliquot of blood was warmed at 37° C. for 5 minutes and hypnotic (from a40 mM in dimethyl sulfoxide stock solution) was added to a finalconcentration of 100 μM. After the desired incubation time, a 150 μlsample was removed and the metabolic reaction was quenched with 150 μlacetonitrile (Sigma-Aldrich, St. Louis, Mo.). Zero time point sampleswere prepared by adding 150 μl acetonitrile to blood prior to addinghypnotic (from a 4 mM in dimethyl sulfoxide stock solution). Thequenched samples were centrifuged and the resultant supernatantseparated and stored at −20° C. until analyzed. Hypnotic concentrationsin thawed samples were determined by high performance liquidchromatography using a Varian Prostar system with a 4.6×250 mm Proto 300C18 column (Nest Group, Southborough, Mass.) with the UV detector set at240 nm. A linear gradient 20% to 45% acetonitrile in water with 0.005%trifluoroacetic acid (Thermo Scientific, Rockford, Ill.) over 20 minuteswas used with a flow rate of 1 ml/min. The lower limit of quantitationof this assay was 3 μM and the precision and accuracy was <10% at 10 μM.

Octanol:Water Partition Coefficients of Etomidate Esters:

One mg of each hypnotic was added to 10 ml of water buffered with 10 mMTris (pH 7.4) and 0.5 ml or 1 ml of octanol. The mixture was stirredovernight and then centrifuged to more fully separate the organic andaqueous phases. The relative hypnotic concentrations in each phase (i.e.the partition coefficient) were determined by high performance liquidchromatography as described for blood.

Statistical Analysis:

Unless indicated otherwise, data are reported as mean+/−SD. Statisticalanalyses were done using Prism v5.0 for the Macintosh (GraphPadSoftware, Inc., LaJolla, Calif.) or Igor Pro 6.1 (Wavemetrics, LakeOswego, Oreg.).

Results and Discussion

Hypnotic Activity of Etomidate Esters:

When administered as an IV bolus to rats, all etomidate esters producedLORR rapidly, dose-dependently, and at the highest doses studied, allrats had LORR. The ED50s for LORR ranged from 0.69±0.04 mg/kg forcyclopropyl-methoxycarbonyl metomidate to 9.6±1.9 forR-methyl-methoxycarbonyl metomidate (FIG. 4 and Table 1). Two rats diedduring our studies after receiving an etomidate ester. One had receiveda 20 mg/kg dose of dimethyl-methoxycarbonyl metomidate, which wassubsequently determined to be 28-fold higher than the ED50 for LORR. Theother rat died after receiving a 20 mg/kg dose ofR-isopropyl-methoxycarbonyl metomidate.

The inventors found no consistent relationship between an etomidateester's potency for producing LORR and its hydrophobicity as reflectedby its octanol:water partition coefficient (Table 1). However for thefour compounds that exist as diastereometric pairs(α-methyl-methoxycarbonyl etomidate, β-methyl-methoxycarbonyl etomidate,methyl-methoxycarbonyl metomidate, and isopropyl-methoxycarbonylmetomidate), the hypnotic potency was higher (ED50 for LORR was lower)for the S form versus the R form. This difference was larger for the twometomidate analogs (methyl-methoxycarbonyl metomidate andisopropyl-methoxycarbonyl metomidate R/S ED50 ratios were 2.7 and 3.0,respectively) versus the two etomidate analogs (α-methyl-methoxycarbonyletomidate and β-methyl-methoxycarbonyl etomidate R/S ED50 ratios were1.7 and 1.2 respectively).

For representative etomidate esters, FIG. 4 plots the duration of LORRas a function of etomidate ester dose on a semi-logarithmic scale. Itdemonstrates that the duration of LORR increased approximately linearlywith the logarithm of the etomidate ester dose. The slope of thisrelationship, which is inversely related to the rate of drug clearancefrom the brain, ranged from 1.0±0.3 for methoxycarbonyl etomidate to12.1±1.1 for 5-isopropyl-methoxycarbonyl metomidate (Table 1).^(21,22)For comparison, this plot also shows the same relationship for etomidateand metomidate, which had slopes of 24±4.7 and Y, respectively.

In Vitro Determination of the Metabolic Half-Life of Etomidate Esters inRat Blood.

To assess the susceptibility of each etomidate ester to metabolism, weadded each compound to rat blood and measured the incubationtime-dependent reduction in etomidate ester concentration. Forrepresentative etomidate esters, FIG. 5 shows that the concentration ofdrug decreased with incubation time in blood in an approximatelyfirst-order manner. We could calculate metabolic half-lives for twelveof the fourteen etomidate esters. Their half-lives ranged from 0.14 min(95% CI 0.31-0.60 min) for methoxycarbonyl etomidate to 8.7 min (95% CI7.4-10.7 min) for dimethyl-methoxycarbonyl metomidate (Table 1).

However in the cases of methoxycarbonyl metomidate andR-methyl-methoxycarbonyl metomidate, metabolism was so fast that theirconcentrations in blood could not be quantified using high performanceliquid chromatography technique after 10 s, the shortest incubationtime. Based on the lower limit of quantification, this indicates ametabolic half-life that is less than 2 s. For comparison, FIG. 5 alsoshows metabolism data for etomidate, which had a calculated metabolichalf-life of 99 min (95% CI 81-126 min).

As with hypnotic potency, the rate of metabolism in blood wasdiastereometrically-selective. For example, the metabolic half-life ofthe S-isopropyl-methoxycarbonyl metomidate was two orders of magnitudelonger than for its R form (Table 1). Similarly, the metabolichalf-lives of S-methyl-methoxycarbonyl metomidate andsa-S-methyl-methoxycarbonyl etomidate were at least four-fold longerthan that of their respective R forms. Only in the case ofβ-methyl-methoxycarbonyl etomidate was there no significant differencein the metabolic half-lives of R and S forms. The current studies showthat introducing aliphatic groups near methoxycarbonyl etomidate'slabile ester moiety modifies the drug's in vitro rate of metabolism inrat blood and in vivo duration of action and hypnotic potency in rats.Furthermore, if the aliphatic group is placed immediately adjacent tothe ester moiety's carbonyl group, the effects on in vitro metabolismand in vivo potency are diastereometrically-selective as each R form ismetabolized in blood more quickly and has a hypnotic potency that islower than its corresponding S form.

The structures of the etomidate esters described in this study are basedon that of methoxycarbonyl etomidate, a soft analog of etomidate thatcontains a metabolically labile ester moiety that is linked to theetomidate ester via a simple two-carbon spacer.¹² We hypothesize thatthis spacer makes the ester labile primarily because it reduces thesteric hindrance that interferes with drug-esterase binding. Themetabolically labile ester is distinct from the existing ester moiety onetomidate which is attached directly to the rigid etomidate imidazolering and is a relatively poor substrate for esterase-catalyzedhydrolysis as evidenced by the long (>1 hour) etomidate in vitrometabolic half-life in rat blood and human s9 liver fraction and severalhour in vivo terminal elimination half-life in humans.^(12,23,24)

TABLE 1 Pharmacodynamic and Pharmacokinetic Properties of Etomidate,Metomidate and Etomidate Esters. Slope of Duration vs. Log Octanol/ Dose± Blood Half- Water ED50 ± SD Life Partition Structure SD min/(log (95%CI) Coefficient ± Number Name mg/kg mg/kg) min SD

Etomidate 0.53 ± 0.17 24.6 ± 4.7 99 (81-126)  800 ± 180*

Metomidate 0.73 ± 0.50 33.0 ± 3.9 143 (124-170)  380 ± 48

Methoxycarbonyl etomidate  5.3 ± 1.5  1.0 ± 0.3 0.41 (0.31-0.60)  190 ±25

α-(R)-methyl- methoxycarbonyl etomidate  5.2 ± 0.5  2.6 ± 0.3 0.19(0.17-0.22)  670 ± 120

α-(S)-methyl- methoxycarbonyl etomidate  3.1 ± 0.4  2.4 ± 0.3 0.76(0.58-1.0)  530 ± 170

α-dimethyl- methoxycarbonyl etomidate  2.4 ± 1  9.8 ± 1.5 2.6 (1.9-4.2)2240 ± 150

β-(R)-methyl- methoxycarbonyl etomidate  3.5 ± 0.6  2.9 ± 0.8 0.91(0.76-1.1)  500 ± 24

β-(S)-methyl- methoxycarbonyl etomidate  2.9 ± 0.3  2.0 ± 0.5 0.72(0.56-0.98)  484 ± 12

β-dimethyl- methoxycarbonyl etomidate  1.9 ± 0.3 11.9 ± 0.6 23.4(19.6-28.9) 1580 ± 40

Methoxycarbonyl metomidate 11.1 ± 0.8  1.6 ± 0.4 <0.03  159 ± 15

(R)-methyl- methoxycarbonyl metomidate  9.6 ± 1.9  4.6 ± 0.7 <0.03  380± 15

(S)-methyl- methoxycarbonyl metomidate  3.5 ± 0.4  1.9 ± 0.2 0.14(0.08-0.62)  330 ± 16

Dimethyl- methoxycarbonyl metomidate 0.72 ± 0.16  9.6 ± 0.8 8.7(7.4-10.7)  660 ± 110

(R)-isopropyl- methoxycarbonyl metomidate  3.6 ± 0.8  6.6 ± 1.3 0.15(0.15-0.16) 3830 ± 310

(S)-isopro- methoxycarpylbonyl metomidate  1.2 ± 0.19 12.1 ± 1.1 15.5(11.6-23.1) 2860 ± 67

Cyclopropyl- methoxycarbonyl metomidate 0.69 ± 0.04  6.9 ± 0.5 0.57(0.49-0.68)  420 ± 11 * From Pejo et al. 8

In Vitro Metabolism in Rat Blood.

The inventors chose blood to measure the metabolic stabilities of theetomidate esters because rat blood has relatively high esterase activityand is thought to be an important (but not the exclusive) site ofetomidate and methoxycarbonyl etomidate metabolism.^(25,26) In order toreduce the rate of ester hydrolysis and prolong the duration of hypnoticaction, the inventors added steric hindrance by adding aliphatic groupsonto the two-carbon spacer of methoxycarbonyl etomidate. This strategywas based on previous studies showing that the presence of bulkychemical groups near metabolically labile ester moieties may slow therate of ester hydrolysis.^(15,27-29) In some cases the inventors alsoshortened the length of the spacer from two carbons to one, formingmetomidate rather than etomidate analogs and found that this acceleratedmetabolism in rat blood. For example, the metabolic half-life ofmethoxycarbonyl etomidate in rat blood is 20 s whereas that ofmethoxycarbonyl metomidate is less than 2 s. Similarly, the metabolichalf-lives of the R and S forms of α-R-methyl-methoxycarbonyl etomidateare at least four-fold longer than the respective R and S forms ofR-methyl-methoxycarbonyl metomidate. This was contrary to what wouldnormally be expected as the shorter spacer is predicted to introducegreater steric hindrance because it brings the labile ester closer tothe rigid imidazole ring. However, the shorter spacer also reduces (to asingle carbon) the distance between the carbonyl group of the labileester moiety and the oxygen of the stable ester (FIG. 1). Such proximitycan allow the oxygen atom, which is electronegative, to more effectivelywithdraw electron density from the carbonyl carbon and thus promotenucleophilic attack by esterases. This mechanism is thought to explainwhy a similarly located chlorine atom—which is alsoelectronegative—increases the rate of acetate ester hydrolysis by40-fold.³⁰

The inventors also discovered that for three of the four diastereometricpairs, the R form was metabolized in rat blood significantly morequickly than the S form. The only diastereometric pair that failed todemonstrate high selectivity was methyl-methoxycarbonyl etomidate. Thiswas also the only pair in which the aliphatic group is not locatedimmediately adjacent to the labile ester moiety, suggesting thatetomidate ester metabolism in blood is most stereoselective when thechiral center is closest to the ester. The stereoselective metabolism inblood that the inventors observed with the etomidate esters isreminiscent of (but larger than) that previously reported for esmolol.³¹In those studies, the blood from different species (e.g. rats and dogs)exhibited differential selectivity for the two enantiomers of esmololand human blood exhibited no selectivity at all.

In Vivo Hypnotic Potency in Rats.

The addition of aliphatic groups onto the spacer increased etomidateester hydrophobicity and altered in vivo etomidate ester hypnoticpotency. However in violation of the Meyer-Overton Rule, increasedhydrophobicity did not correlate with increased potency implying thatthe interactions between etomidate esters and their relevant moleculartarget (presumably the γ-aminobutyric acid receptor) are structurallyspecific. Analogous conclusions have previously been made for propofolanalogs.³² The data presented herein also suggests that hypnotic potencycan be modestly diastereometrically-selective as all R forms of theetomidate esters had modestly lower hypnotic potencies than theirrespective S forms. Without wishing to be bound by a theory, this canresult from their lower intrinsic potencies (i.e. potencies at theγ-aminobutyric acid receptor) or their faster metabolism. The latter canbe important if ultra-rapid metabolism in blood lowers the concentrationof drug that reaches the brain following bolus injection.

Unexpectedly, four compounds (dimethyl-methoxycarbonyl metomidate,cyclopropyl-methoxycarbonyl metomidate, cyclobutyl-methoxycarbonylmetomidate and cyclopentyl-methoxycarbonyl metomidate) had potenciesthat were nearly an order of magnitude higher than that ofmethoxycarbonyl etomidate and similar to that of etomidate. The firsttwo of these compounds were also determined to possess in vitrometabolic half-lives intermediate between those of methoxycarbonyletomidate and etomidate and all four compounds exhibited in vivodurations of action intermediate between those of methoxycarbonyletomidate and etomidate.

Methoxycarbonyl etomidate is the prototypical rapidly metabolizedetomidate analog; however, preliminary studies suggest that it may betoo short acting for some clinical uses. The inventors hypothesized thatthe metabolism rate and duration of action of methoxycarbonyl etomidatecould be systematically reduced and its clinical utility improved byincorporating specific aliphatic groups into the molecule to stericallyprotect its ester moiety from esterase-catalyzed hydrolysis. To testthis hypothesis, the inventors designed, synthesized, and studied aseries of methoxycarbonyl etomidate analogs (etomidate esters)containing various aliphatic protecting groups.

Etomidate esters were synthesized and their hypnotic potencies anddurations of action following bolus administration were measured in ratsusing a loss of righting reflexes assay. Etomidate ester octanol:waterpartition coefficients and metabolic half-lives in pooled rat blood weredetermined chromatographically.

Etomidate esters produced hypnosis rapidly and in a dose-dependentmanner. ED50s for loss of righting reflexes ranged from 0.69±0.04 mg/kgfor cyclopropyl-methoxycarbonyl metomidate to 9.6±1.9 forR-methyl-methoxycarbonyl metomidate and did not correlate withoctanol:water partition coefficients. The slope of a plot of theduration of loss of righting reflexes versus the logarithm of theetomidate ester dose ranged 12-fold among etomidate esters implyingwidely varying brain clearance rates. Etomidate ester in vitro metabolichalf-lives varied by more than an order of magnitude and werediastereometrically-selective. Thus, addition of aliphatic protectinggroups adjacent to the labile ester moiety of etomidate esters can beused to optimize their hypnotic potencies, durations of action, andrates of metabolism.

Accordingly, data presented in this study shows that addition ofaliphatic groups adjacent to the labile ester moiety of etomidate esterscan be used to optimize their hypnotic potencies, durations of action,and rates of metabolism. The introduction of aliphatic groups near anetomidate ester's metabolically-labile ester moiety modifies the drug'srate of metabolism in blood and duration of action and hypnotic potencyin rats. Furthermore, the effects of these groups areenantiomerically-selective.

Example 2 Synthesis of Compounds

Preparation of Compound 8:

To a solution of 1 (700 mg, 10 mmol) in THF (50 mL) was added Me₃SiCN(1.39 g, 14 mmol) and ZnI (90 mg, 0.28 mmol). After stiffing 24 h at RT,the reaction mixture was evaporated. The residue was diluted with EtOAc,washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (hexane/EtOAc 10:1 to 3:1) to give 2 (530 mg, 55%).

A solution of 2 (533 mg, 5.5 mmol) in AcOH (25 mL) and conc. HCl (25 mL)was refluxed for 3 h. The reaction mixture was evaporated. The residuewas purified by silica gel column chromatography (DCM/MeOH 20:1 to 5:1)to give 3 (510 mg, 80%).

A solution of 2 (500 mg, 4.3 mmol) in MeOH (10 mL) and p-TsOH (100 mg)was refluxed for 24 h. The reaction mixture was evaporated. The residuewas purified by silica gel column chromatography (hexane/EtOAc 3:1) togive 4 (206 mg, 37%).

To a solution of 5 (12.2 g, 50 mmol) in MeOH/THF (1:1) (150 mL) wasadded aqueous LiOH (2N, 200 mL) at room temperature and the mixture wasstirred overnight. After removal of MeOH/THF, the resulting aqueousphase was washed with ether, acidified with dilute HCl (pH=4), andextracted with dichloromethane. The combined organic extracts werewashed with water, brine, and dried over Na₂SO₄, filtered, andconcentrated. The residue was solidified and filtered to yield thecorresponding acid 6 (10.8 g, 81%).

To a solution of 6 (285 mg, 1.32 mmol) in DCM (15 mL) was added (COCl)₂(350 μL) at 0° C. drop-wise. The reaction mixture was stirred at roomtemperature until completion of the reaction monitored by HPLC. Thereaction mixture was then concentrated and azeotroped by anhydroustoluene three times. The crude product 7 was dried on high vacuum pumpfor 3 h before use for the next step directly without storage.

To a solution of 7 from Step 5 (1.32 mmol) in DCM (20 mL) was added 4(200 mg) in 5 mL of DCM followed by Et₃N (800 μL) at 0° C. The reactionmixture was stirred at room temperature for 48h. The reaction mixturewas diluted with EtOAc, washed with water, brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography (hexane/EtOAc 3:1 to 1:1) to give 8 (45 mg,10.4%). LCMS ES⁺[M+1]=329. ¹H NMR (400 MHz, CDCl3) δ 8.00 (S, 1H), 7.95(s, 1H), 7.35-7.42 (m, 3H), 7.22-7.29 (m, 2H), 6.35 (q, J=7.2 Hz, 1H),3.72 (s, 3H), 2.75-2.79 (m, 2H), 2.4-2.47 (m, 2H), 2.07-2.11 (m, 2H),1.92 (d, J=7.2 Hz, 3H), 1.5-1.54 (m, 2H).

Preparation of Compound 9:

A solution of sodium metabisulfate (4.84 g, 0.025 mol) in distilledwater (20 mL) was added over 45 min to a stirred mixture ofcyclopentanone 1 (3.45 g, 0.041 mol), potassium cyanide (3.3 g, 0.051mol), and water (20 mL). The mixture was stirred at 25° C. for 6 hrs.The mixture was extracted with ethyl acetate (2×100 mL) and the organicsdried (MgSO₄), and concentrated to give 3.6 g ofα-hydroxycyclopentanecarbonitrile as an oil. The oil was dissolved inacetic acid (12.5 mL) and the solution was diluted with concentrated HCl(37.5 mL). The solution was refluxed for 3 hrs and concentrated to anoily residue that was partitioned between water (50 mL) and EtOAc (50mL). The organic phase was separated, dried (MgSO₄), and concentrated toan oily residue which solidified on standing to give 4.1 g ofα-hydroxycyclopentanecarboxylic acid. This material was dissolved inMeOH (50 mL) and treated with concentrated sulfuric acid (1 drop). Thesolution was refluxed for 12 hrs and concentrated to an oily residuewhich was dissolved in EtOAc (50 mL) and washed with a 5% solution ofsodium bicarbonate (50 mL). The organics were dried (MgSO₄), filtered,concentrated, and chromatographed on silica gel (80% Hexanes/20% EtOAc)to give α-hydroxycyclopentanecarboxylic acid methyl ester 2 (3.66 g) asan clear colorless oil.

A solution of 2 (265 mg, 1.8 mmol) in dry pyridine (10 mL) was heated to80° C. and a solution of 3 (243 mg, 0.9 mmol) in anhydrousdichloromethane (10 mL) was dropwise added over a 1 hour period using asyringe pump. The resulting suspension was evaporated and diluted with1N HCl (30 mL) and EtOAc (50 mL). The organics were dried (MgSO₄),filtered, and concentrated to give an oily residue which waschromatographed on silica gel (60% Hexanes/40% EtOAc) to give 9 as anoil: (140 mg). ¹HNMR (400 MHz, CDCl₃): δ 1.71-1.79 (4H, m), 1.81-1.91(3H, d, J=3.1 Hz), 2.01-2.17 (2H, m), 2.19-2.39 (2H, m), 3.61 (3H, s),6.27 (1H, m), 7.13-7.19 (2H, m), 7.22-7.37 (3H, m), 7.72 (1H, s), 7.81(1H, s). LCMS (mobile phase: 2%-98% Acetonitrile-Water-0.1% Formicacid): purity is >95%, Rt=2.5 min; MS Calcd.: 342; MS Found: 343 (M+1).

Preparation of Compound 10:

A solution of sodium metabisulfate (4.84 g, 0.025 mol) in distilledwater (20 mL) was added over 30 min to a stirred mixture ofcyclohexanone 1 (4.02 g, 0.041 mol), potassium cyanide (3.3 g, 0.051mol), and water (20 mL). The mixture was stirred at 25° C. for 8 hrs.The mixture was extracted with ethyl acetate (2×100 mL) and the organicsdried (MgSO₄), and concentrated to give 3.8 g ofα-hydroxycyclohexanecarbonitrile as an oil. The oil was dissolved inacetic acid (12.5 mL) and the solution was diluted with concentrated HCl(37.5 mL). The solution was refluxed for 6 hours and concentrated to anoily residue that was partitioned between water (50 mL) and EtOAc (50mL). The organic phase was separated, dried (MgSO₄), and concentrated toa solid. The solid was washed with hexanes (25 mL) and filtered to give2.84 g of α-hydroxycyclohexanecarboxylic acid. This material wasdissolved in MeOH (50 mL) and treated with concentrated sulfuric acid (1drop). The solution was refluxed for 16 hours and concentrated to anoily residue which was dissolved in EtOAc (50 mL) and washed with a 5%solution of sodium bicarbonate (50 mL). The organics were dried (MgSO₄),filtered, concentrated, and chromatographed on silica gel (80%Hexanes/20% EtOAc) to give α-hydroxycyclohexanecarboxylic acid methylester 2 (2.71 g) as an clear colorless oil.

A solution of 2 (350 mg, 2.2 mmol) in dry pyridine (10 mL) was heated to80° C. and a solution of 7 (300 mg, 1.1 mmol) in anhydrousdichloromethane (10 mL) was added drop-wise over a 1-hour period using asyringe pump. The resulting suspension was evaporated and diluted with1N HCl (30 mL) and EtOAc (50 mL). The organics were dried (MgSO₄),filtered, and concentrated to give an oily residue which waschromatographed on silica gel (60% Hexanes/40% EtOAc) to give 10 as anoil: (161 mg). ¹HNMR (400 MHz, CDCl₃): δ 1.21-1.38 (2H, m), 1.42-1.78(4H, m), 1.79-1.85 (1H, m), 1.85 (3H, d, J=2.7 Hz), 3.05-3.28 (3H, m),3.58 (3H, s), 6.25 (1H, m), 7.13-7.18 (2H, m), 7.23-7.39 (3H, m), 7.71(1H, s), 7.82 (1H, s). LCMS (mobile phase: 2%-98%Acetonitrile-Water-0.1% Formic acid): purity is >95%, Rt=2.1 min; MSCalcd.: 356; MS Found: 357 (M+1).

Preparation of Compound 11:

A solution of 9 (500 mg, 4.3 mmol) in MeOH (10 mL) and p-TsOH (100 mg)was refluxed for 24h. The reaction mixture was evaporated. The residuewas purified by silica gel column chromatography (hexane/EtOAc 3:1) togive 10 (182 mg, 33%).

To a solution of 6 (216 mg, 1 mmol) in DCM (15 mL) was added (COCl)₂(150 μL) at 0° C. drop-wise. The reaction mixture was stirred at roomtemperature until completion of the reaction monitored by HPLC. Thereaction mixture was then concentrated and azeotroped by anhydroustoluene three times. The crude product 7 was dried on high vacuum pumpfor 3h before use for the next step directly without storage.

To a solution of 7 from Step 5 (1 mmol) in DCM (15 mL) was added 10 (156mg, 1.2 eq) in 5 mL of DCM followed by Et3N (400 μL) at 0° C. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with EtOAc, washed with water, brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel column chromatography (hexane/EtOAc 3:1 to 1:1) to give 11 (203 mg,61%). LCMS ES⁺[M+1]=329.

Preparation of Compound 12:

A solution of sodium metabisulfate (14.5 g, 0.075 mol) in distilledwater (60 mL) was added over 2h to a stirred mixture of 1 (23.2 g, 123mmol), potassium cyanide (9.9 g, 153 mmol), and water (60 mL). Themixture was stirred at 25° C. for 5 hours. The mixture was extractedwith ethyl acetate (2×100 mL) and the organics dried (MgSO₄), andconcentrated to give an oil which slowly solidified on standing at RT.The waxy solid was triturated with hexanes-ether (9:1) and filtered togive 14.9 g of the corresponding cyanohydrin. This solid was dissolvedin acetic acid (25 mL) and the solution was diluted with concentratedHCl (75 mL). The solution was refluxed for 3 hours and concentrated to asolid mass. Toluene (100 mL) was added to the solid mass and the mixturewas evaporated. This process was repeated one additional time. Theresulting solid was then diluted with MeOH (100 mL) and treated withconcentrated sulfuric acid (3.4 g). The solution was refluxed for 12hours and concentrated to an oily residue which was diluted with asaturated solution of sodium bicarbonate (100 mL) and then extractedwith EtOAc (2×100 mL). The organics were dried (MgSO₄), filtered,concentrated, and chromatographed on silica gel (60% hexanes/40% EtOAc)to give 2 (11.2 g) as an amber oil.

This oil 2 (11.2 g) was dissolved in MeOH (40 mL), treated with Pd—C(5%,1.5 g), acetic acid (2.7 g), and then shaken under 50 psi hydrogen for 2hours. The suspension was filtered through a pad of celite andconcentrated to an oily residue. The oil was dissolved in EtOAc (50 mL),and the solution was treated with a saturated solution of sodiumbicarbonate (50 mL). The mixture was vigorously stirred anddi-tert-butyl dicarbonate (19.6 g, 90 mmol) was added drop-wise as asolution in EtOAc (20 mL). The mixture continued stirring for 2 hoursand the organics were separated, concentrated, and chromatographed onsilica gel to give 11 g of 3 as an oil.

A solution of 3 (1.5 g, 5.8 mmol) in dry pyridine (25 mL) was heated to80° C. and a solution of 3 (1 g, 3.6 mmol) in anhydrous dichloromethane(25 mL) was added drop-wise over a 2 hour period using a syringe pump.The resulting suspension was evaporated and diluted with 1N HCl (30 mL)and EtOAc (50 mL). The organics were dried (MgSO₄), filtered, andconcentrated to give an oily residue which was chromatographed on silicagel (60% Hexanes/40% EtOAc) to give an oil which was dissolved in EtOAc(5 mL) and the resulting solution added to a vigorously stirred solutionof HCl in dioxane (4N, 3 mL). The suspension was stirred for 1 hour atRT and the solid filtered, washed with ether and dried to give 12 as thedihydrochloride salt, a white solid (850 mg). ¹HNMR (400 MHz, DMSO): δ1.85 (3H, d, J=2.9 Hz), 2.01-2.25 (4H, m), 2.96-3.27 (4H, m), 3.47 (3H,s), 6.21 (1H, m), 7.18-7.22 (2H, m), 7.23-7.41 (3H, m), 8.61 (1H, s),9.31 (1H, s). LCMS (mobile phase: 2%-98% Acetonitrile-Water-0.1% Formicacid): purity is >99%, Rt=0.66 min; MS Calcd.: 357; MS Found: 358 (M+1)

Preparation of Compound 13:

To a solution of 12 dihydrochloride (500 mg, 1.2 mmol) in CH₃CN (5 mL)was added paraformaldehyde (360 mg, 12 mmol) and the suspension wasallowed to stir for 30 minutes. NaCNBH₃ (189 mg, 3 mmol) was then addedand the resultant mixture was stirred for 2 hours. The solution wasdiluted with EtOAc (50 mL) and washed with a saturated sodiumbicarbonate solution (100 mL). The organics were washed with water (50mL) and brine (50 mL) and then dried (MgSO₄), filtered, concentrated,and chromatographed on silica gel (EtOAc) to give 107 mg of 13 as anoil. This material was dissolved in EtOAc (2 mL) and added drop-wise toa stirred solution of HCl in dioxane (4N, 1 mL). The suspension wasstirred for 1 hour and the solids were filtered and dried to give 98 mgof 13 as the dihydrochloride. ¹HNMR (400 MHz, DMSO): δ 1.91 (3H, d,J=1.7 Hz), 2.19-2.41 (4H, m), 2.76 (3H, d, J=1.2 Hz), 3.05-3.26 (2H, m),3.28-3.61 (2H, m), 3.49 (3H, s), 6.23 (1H, m), 7.21-7.24 (2H, m),7.25-7.39 (3H, m), 8.49 (1H, s), 9.31 (1H, s). LCMS (mobile phase:2%-98% Acetonitrile-Water-0.1% Formic acid): purity is >98%, MS Calcd.:371; MS Found: 372 (M+1)

Preparation of Compound 14:

To a chilled solution (0° C.) of NaCN (25 g, 500 mmol) in water (75 mL)was added drop-wise via syringe pump a solution of 1 (5 g, 50 mmol) inconcentrated HCl (450 g) over the course of 2 hours keeping thetemperature at 0° C. The resulting solution was allowed to stir for anadditional 16 hours at RT and the pH was adjusted to 4 usingconcentrated HCl. The resulting suspension was extracted with ether(3×100 mL). The organics were combined, washed with a saturated sodiumbicarbonate solution, dried (MgSO₄), filtered, and concentrated to anoil, which was dissolved in acetic acid (25 mL) and diluted withconcentrated HCl (75 mL). The solution was refluxed for 6 hours andconcentrated to an oily residue that was partitioned between water (100mL) and EtOAc (100 mL). The organic phase was separated, washed with asodium bicarbonate solution (5%), dried (MgSO₄), and concentrated to anoily residue which was dissolved in MeOH (50 mL) and treated withconcentrated sulfuric acid (3 drops). The solution was refluxed for 12hours and concentrated to an oily residue which was dissolved in EtOAc(50 mL) and washed with a 5% solution of sodium bicarbonate (50 mL). Theorganics were dried (MgSO₄), filtered, concentrated, and chromatographedon silica gel (70% hexanes/30% EtOAc) to give 2 (2.8 g) as a clearcolorless oil.

A solution of 2 (500 mg, 3.1 mmol) in dry pyridine (15 mL) was heated to80° C. and a solution of 7 (423 mg, 1.6 mmol) in anhydrousdichloromethane (15 mL) was added drop-wise over 1 hour using a syringepump. The resulting suspension was evaporated and diluted with 1N HCl(50 mL) and EtOAc (80 mL). The organics were dried (MgSO₄), filtered,and concentrated to give an oily residue which was chromatographed onsilica gel (60% hexanes/40% EtOAc) to give 14 as an oil: (330 mg). ¹HNMR(400 MHz, CDCl₃): δ 1.82 (3H, d, J=5.2 Hz), 2.00-2.27 (4H, m), 3.58 (3H,s), 3.61-3.94 (4H, m), 6.25 (1H, m), 7.13-7.19 (2H, m), 7.21-7.39 (3H,m), 7.78 (1H, s), 7.82 (1H, s). LCMS (mobile phase: 2% -98%Acetonitrile-Water-0.1% Formic acid): purity is >95%, Rt=3.1 min; MSCalcd.: 358; MS Found: 359 (M+1)

Preparation of Compound 16:

To a solution of 6 (648 mg, 3 mmol) in DCM (50 mL) was added (COCl)₂(400 μL) at 0° C. drop-wise. The reaction mixture was stirred at roomtemperature until completion of the reaction monitored by HPLC. Thereaction mixture was then concentrated and azeotroped by anhydroustoluene three times. The crude product 7 was dried on high vacuum pumpfor 3h before use for the next step directly without storage.

To a solution of 7 from Step 5 (3 mmol) in DCM (50 mL) was added 12 (203mg, 1 eq) followed by Et₃N (400 μL) at 0° C. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith EtOAc, washed with water, brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (hexane/EtOAc 1:1 to 0:1) to give 13 (375 mg, 42%).

To a solution of 13 (250 mg, 0.83 mmol) in DCM (5 mL) was added (COCl)₂(100 μL) at 0° C. drop-wise. The reaction mixture was stirred at roomtemperature until completion of the reaction monitored by HPLC. Thereaction mixture was then concentrated and azeotroped by anhydroustoluene three times. The crude product 14 was dried on high vacuum pumpfor 3h before use for the next step directly without storage.

To a solution of 14 from Step 3 (0.83 mmol) in DCM (10 mL) was added 15(20 mg) followed by Et₃N (100 μL) at 0° C. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith EtOAc, washed with water, brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (hexane/EtOAc 1:1 to 0:1) to give 16 (65 mg, 22%). LCMSES⁺[M+1]=366. ¹H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.90 (s, 1H),7.35-7.41 (m, 3H), 7.20-7.29 (m, 2H), 6.37 (q, J=6.8 Hz, 1H), 5.32-5.46(m, 1H), 4.81-4.85 (m, 2H), 4.48-4.51 (m, 2H), 1.92 (d, J=6.8 Hz, 3H),1.6-1.67 (m, 2H), 1.32-1.35 (m, 2H).

Preparation of Compound 20:

To a solution of 6 (216 mg, 1 mmol) in DCM (15 mL) was added (COCl)₂(150 μL) at 0° C. drop-wise. The reaction mixture was stirred at roomtemperature until completion of the reaction monitored by HPLC. Thereaction mixture was then concentrated and azeotroped by anhydroustoluene three time. The crude product 7 was dried on high vacuum pumpfor 3h before use for the next step directly without storage.

To a solution of 7 from Step 1 (1 mmol) in DCM (15 mL) was added 19 (117μL) in 5 mL of DCM followed by Et₃N (420 μL) at 0° C. The reactionmixture was stirred at room temperature overnight. The reaction mixturewas diluted with EtOAc, washed with water, brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography (hexane/EtOAc 3:1 to 1:1) to give 20 (265 mg,88%). LCMS ES⁺[M+1]=301. ¹H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.90(s, 1H), 7.35-7.41 (m, 3H), 7.20-7.29 (m, 2H), 6.37 (q, J=6.8 Hz, 1H),5.32-5.46 (m, 1H), 4.81-4.85 (m, 2H), 4.48-4.51 (m, 2H), 1.92 (d, J=6.8Hz, 3H), 1.6-1.67 (m, 2H), 1.32-1.35 (m, 2H).

In vivo Testing

Animals:

Animals were housed in a dedicated room at the vivarium of VivoPathInc., located at Redstone Center, 55 Union Street, Worcester, Mass.Housing and care was as specified in the USDA Animal Welfare Act (9 CFR,Parts 1, 2, and 3) and as described in the Guide for the Care and Use ofLaboratory Animals from the National Research Council. Environmentalconditions of housing rooms are set at the following ranges:temperature: 70±7° F. (22±4° C.), humidity: 50±20%, light cycle: 12-hourlight/12-hour dark cycle—lights on at 7 am and off at 7 pm, air changes:ten or more air changes per hour with 100% fresh air. The animals' bodyweights were measured prior to the first dose on each experimental day.

Mice:

Adult ICR mice (20-30 g) were purchased from Harlan (South Easton,Mass.). Drugs were administered as intravenous bolus injection in a tailvein.

Rats:

Adult male Sprague-Dawley rats (225-300 g) were purchased from Harlan(South Easton, Mass.). Drugs were administered as an intravenous bolusinjection through a jugular venous catheter pre-implanted by the vendorprior to animal delivery to the animal care facility.

Drug Testing:

Drugs were prepared in either dimethylsulfoxide/saline or saline vehicleor hydroxypropyl-β-cyclodextrin (20% in water, pH 7.0) solution and wereadministered as an intravenous bolus injection. Animals received 1-4doses of drug(s) during an experimental day, either ascending doses ordifferent drugs. Doses were administered at intervals equal to thelonger of 1 h or 10-times the duration of apparent sedative/hypnoticeffects from the previous dose. The sedative/hypnotic properties of thedrugs were evaluated by observation of the rats, ranging from mildexcitation, mild sedation apparent due to reduced activity, and moderatesedation to hypnosis reflected by loss of righting reflex (LORR, theability to place rear and hind legs under the body, as well asattenuation/loss of nociceptive reflexes).

Results:

The results of the in vivo testing of representative novel etomidateanalogues are shown in Table 2, below, and illustrated in FIGS. 6 and 7,in comparison with etomidate and other analogues. For representativeetomidate esters FIGS. 6 and 7 plot the duration of LORR as a functionof etomidate ester dose on a semi-logarithmic scale in mice and rats,respectively. They demonstrate that the duration of LORR increasedapproximately linearly with the logarithm of the etomidate ester dose.The slope of this relationship was approximately 1.0 formethoxycarbonyl-etomidate in both mice and rats. For etomidate, theslope was approximately 10 in mice and 24 in rats.Cyclopropyl-MOC-metomidate exhibited intermediate dose-dependency, withslope approximately 7 in mice and 10 in rats. Cyclobutyl-MOC-metomidateexhibited similar dose-dependency, with slope approximately 7 in miceand 5 in rats.

TABLE 2 Structure Mouse response Rat response

No effect at 4 mg/kg IV Not tested

Mild excitation but no sedation at 2, 4 or 8 mg/kg IV Not tested

Sedation/hypnosis induced at 2, 4 & 8 mg/kg IV ED₅₀ ~1-2 mg/kg SeeFigure 6 Sedation/hypnosis induced at 1, 2, 4 & 8 mg/kg IV ED₅₀ ~1 mg/kgSee Figure 7

Not tested Sedative at 1 & 2 mg/kg, with rear paws out but head andforepaws mobile Hypnotic at 4 & 8 mg/kg, quitelong-acting

Not tested Mildly sedative at 4 mg/kg Hypnotic at 8 mg/kg — deep andlong-acting

Not tested No effect apparent at 4, 8 & 16 mg/kg

Not tested No effect apparent at 4, 8 & 16 mg/kg

Not tested Mildly sedative at 16 mg/kg More profound short-actingsedation at 32 mg/kg

Sedation/hypnosis induced at 8, 16 & 32 mg/kg IV ED₅₀ ~8 mg/kg Nottested

Sedation/hypnosis induced at 2 & 4 mg/kg IV ED₅₀ ~0.7 mg/kg See Figure 6Sedation/hypnosis induced at 2 & 4 mg/kg IV ED₅₀ ~0.7 mg/kg See Figure 7

Sedation/hypnosis induced at 16 & 32 mg/kg IV ED₅₀ ~10 mg/kg See Figure6 Sedation/hypnosis induced at 8 & 16 mg/kg IV ED₅₀ ~8 mg/kg See Figure7

Sedation/hypnosis induced at 2 & 4 mg/kg IV ED₅₀ ~0.7 mg/kg See Figure 6Sedation/hypnosis induced at 2 & 4 mg/kg IV ED₅₀ ~0.7 mg/kg See Figure 7Cyclopropyl-MOC-Metomidate—Various In Vitro and In Vivo Assessments

Cyclopropyl-MOC-metomidate induces anesthesia by acting as a positiveallosteric modulator of the γ-aminobutyric acid (GABA) type A (GABA_(A))receptor. Cyclopropyl-MOC-metomidate and its principle metabolite,CPM-acid, were evaluated for their ability to potentiate activation ofGABA_(A) receptor current in Xenopus oocytes expressing the humanα₁(L264T), β₂ and γ_(2L) subunits of the GABA_(A) receptor usingestablished methods (Ge et al., 2011). The α₃(L264T)β₂γ_(2L) mutant wasused rather than wild-type GABA_(A) receptor because it is directlyactivated by anesthetics, allowing a simpler assessment of the drugpotency without the need for concomitant activation by GABA. Anestheticpotency on this mutated GABA_(A) receptor is similar to that onwild-type receptors. Currents were recorded using conventional2-electrode voltage clamp technique at a holding potential of −50 mV.Oocytes were placed in a 0.04-mL recording chamber and constantlyperfused at a rate of 4-6 mL/min. The current response to ABP-700 orCPM-acid was normalized to that produced by 100 μM GABA in the sameoocyte and data presented as mean±SD from 3-6 oocytes.

Cyclopropyl-MOC-metomidate enhanced GABA-induced current having minimaleffects at ˜0.3 μM and an EC₅₀ value of 5.8±1.1 μM. CPM-acid was˜1000-fold less potent, having minimal effects at ˜100 μM and an EC₅₀value extrapolated to be near 14 mM. The range of plasmacyclopropyl-MOC-metomidate concentrations associated with anesthesia is˜0.2-3 μM, corresponding to ˜EC₅₋₄₀ values observed in the oocyte GABAcurrent.

Cyclopropyl-MOC-metomidate (10 μM) was screened for its ability toinhibit radioligand binding in assays of 68 receptors, ion channels andtransporters. No significant effect of cyclopropyl-MOC-metomidate wasobserved. Binding of each radioligand to its receptor was inhibited nomore than 25%. Of note, cyclopropyl-MOC-metomidate had no effect on thebinding of either [³H]-flunitrazepam (a benzodiazepine) or [³H]-muscimol(a GABA_(A) receptor agonist) to the GABA_(A) receptor channel.

Cyclopropyl-MOC-metomidate was administered to rats as an IV bolus atdoses of 0.25, 0.5, 1, 2, 4, 8, 16 or 24 mg/kg. Rats were monitored foranesthesia as assessed by loss of righting reflex (LORR) and thesubsequent time to recovery from LORR. Bolus doses of 1.0 mg/kg andgreater induced dose-dependent anesthesia. The minimum effective bolusanesthetic dose in rats was approximately 1 mg/kg based on LORRobservations. Time to recovery from LORR was dose-dependent. A bolusdose of 4 mg/kg induced 3-8 minutes of anesthesia and LORR and wasselected as an effective and convenient induction dose to precedecontinuous infusion dosing.

Cyclopropyl-MOC-metomidate anesthesia in rats by continuous infusionwithout a bolus induction dose was examined in this study. An infusionof 4 mg/kg induced anesthesia after approximately 3 minutes as measuredby LORR. Recovery of righting reflex took approximately 4 minutesfollowing infusion discontinuation whether the infusion was conductedfor 5 or 120 minutes. Due to the prolonged onset of anesthesia,continuous infusion for anesthesia induction in rats was judged to besuboptimal for most experimental circumstances, and all subsequentstudies were conducted using a bolus induction dose of 3-4 mg/kg.

Cyclopropyl-MOC-metomidate continuous infusion studies were conducted todetermine the minimum effective infusion dose required to induceanesthesia. Anesthesia was induced in rats with a 4 mg/kg IV bolus dosefollowed by continuous infusion of cyclopropyl-MOC-metomidate at 1mg/kg/min. When stable anesthesia was observed after 30 minutes ofinfusion, the infusion rate was reduced to 0.8 mg/kg/min and then to 0.6mg/kg/min and 0.4 mg/kg/min at 30-minute intervals. Anesthesia and LORRwas maintained in all rats at 0.6 mg/kg/min. At 0.4 mg/kg/min all threerats exhibited signs of lightening of anesthesia. In one rat, theinfusion at 0.4 mg/kg/min was discontinued after 7 minutes due toinadequate the anesthesia. The other two rats received the full30-minute infusion at 4 mg/kg/min with no further change. Rats recoveredfrom LORR and resumed normal behavior within 2-6 minutes of stopping theinfusion. Based on these observations, the minimum effective infusiondose rate required to maintain anesthesia was determined to beapproximately 0.5 mg/kg/min. An independent assessment of “minimalimmobilizing infusion rate” of cyclopropyl-MOC-metomidate in ratsyielded a value of 0.89±0.18 mg/kg/min.

To determine the anesthetic effects of cyclopropyl-MOC-metomidate inbeagle dogs, animals received single IV bolus doses of 0.25, 0.5, 1, 2,4, 8 or 16 mg/kg. Anesthesia induction was deemed to occur when dogslost consciousness and muscle tone, could be placed in a laterallyrecumbent position, and exhibited little or no response to externalstimuli.

Cyclopropyl-MOC-metomidate doses of 1.0 mg/kg and greater producedanesthesia in the dogs and the time to return of normal behavior wasdose-dependent and similar to that observed in rat. The minimallyeffective anesthetic dose (MED) in dogs was approximately 1 mg/kg. Abolus dose of 3 or 4 mg/kg induced 3-6 minutes of anesthesia and wasselected as an effective and convenient induction dose prior tocontinuous infusion dosing. A pilot study was conducted in dogs toassess anesthesia induced by cyclopropyl-MOC-metomidate continuousinfusion without a bolus induction dosing. Two dogs receivedcyclopropyl-MOC-metomidate as a 1 mg/kg/min IV infusion without priorbolus administration. Anesthesia onset was observed between 2.5-4.0minutes after initiation of infusion. Due to the prolonged onset ofanesthesia, infusion for anesthesia induction in dogs was judged to besuboptimal for most experimental circumstances, and all subsequentstudies were conducted using a IV bolus induction dose of 3-4 mg/kg.

Continuous infusion studies were conducted in 2 dogs by firstadministering a 4 mg/kg bolus induction dose followed by continuousinfusion of cyclopropyl-MOC-metomidate at 1 mg/kg/min. Anesthesiainduction was determined using the methods described above. When stableanesthesia was observed after 20-30 minutes of infusion, the infusionrate was reduced incrementally at 10-minute intervals: Dog 1:0.8-0.5-0.4-0.3 mg/kg/min; Dog 2: 0.7-0.5-0.3 mg/kg/min). Anesthesia wasmaintained in both dogs at 0.5 mg/kg/min, but was judged to be light at0.3-0.4 mg/kg/min based on spontaneous movements and response tostimuli. The time to emergence from anesthesia and recovery of normalbehavior was rapid and did not vary markedly as a function of theduration of the infusion in the range of 0.5-1 mg/kg/min. The minimumeffective (anesthetic) continuous infusion dose rate (infusion MED) ofcyclopropyl-MOC-metomidate in dogs was estimated to be approximately 0.5mg/kg/min. The dog infusion MED was then confirmed in 4 dogs in thatfirst received a 3 mg/kg IV bolus induction dose followed by continuousinfusion at 0.5 mg/kg/min for 120 minutes.

Importantly, dogs emerged from cyclopropyl-MOC-metomidate anesthesia inapproximately 5 minutes and recovered apparently normal behavior within10-12 minutes, whether they had received a 4 mg/kg bolus dose or a 4mg/kg bolus dose bolus induction followed continuous infusion of 0.5mg/kg/min for 30 or 120 minutes.

Recovery from anesthesia with cyclopropyl-MOC-metomidate is therefore“context-independent” at effective dose ranges, in contrast with theresponse to other anesthetics. The sedative/hypnotic response and timeof emergence and recovery of dogs to cyclopropyl-MOC-metomidate wascompared to etomidate and propofol, two commonly used anesthetic agents.

Etomidate was administered to dogs at IV bolus doses ranging from 0.25to 2 mg/kg. Anesthesia in the dogs was measured as described above.Bolus injections of etomidate induced anesthesia in the range 0.5-2mg/kg. The bolus dose of 2 mg/kg was adopted to induce anesthesia priorto subsequent continuous infusions.

For continuous infusions, a minimum initial dose rate of 0.15 mg/kg/minwas found to be effective. However, after approximately 30 minutes ofinfusion it was necessary to decrease the infusion rate to 0.1 mg/kg/mindue to a decrease in respiratory rate. Emergence and complete recoveryfrom etomidate anesthesia was longer than for cyclopropyl-MOC-metomidateand exhibited marked context-dependency, such that recovery from30-minute or 120-minute continuous infusion was considerably prolongedrelative to recovery from a bolus dose. Notably, dogs experiencedextended periods of involuntary movements during the extended period ofrecovery from etomidate anesthesia.

Propofol was administered to dogs as an IV bolus dose of 5 mg/kg toinduce anesthesia followed by a continuous infusion at 0.4 mg/kg/min.Dogs emerged from anesthesia approximately 15 minutes after the end ofinfusion and recovered normal behavior 30 minutes or more afterinfusion. Recovery from 120-minute propofol infusion was approximately3-fold longer than recovery from a cyclopropyl-MOC-metomidate infusionof the same duration.

A well-described in vivo model (Cotton et al., 2009; Pessina et al.,2009) was employed to compare the effects of cyclopropyl-MOC-metomidatewith vehicle, etomidate and propofol upon adrenal steroid response to aprovocative challenge. Dexamethasone (0.01 mg/kg) was administered twohours before the first administration of ACTH and re-administered every2 hours to maintain suppression. Dexamethasone pretreatment suppressesthe hypothalamo-hypophyseal axis to prevent endogenous ACTH release andsubsequent adrenocortical steroid secretion. During dexamethasonesuppression, the test substance (cyclopropyl-MOC-metomidate, etomidate,propofol or vehicle) was administered for 30 or 120 min. Synthetic ACTH(Synacthen, 250 μg) was then administered at times after test substanceadministration to evaluate the effects of the test substance on therelease of the adrenal steroid, cortisol. Twenty-two hours afteradministration of the test substance, dexamethasone was againadministered and a single ACTH injection was administered to testadrenal function 24 hours after test substance administration.

The series of studies described below demonstrates thatcyclopropyl-MOC-metomidate inhibit adrenal cortisol production onlyduring and immediately after their infusion. Normal adrenalresponsiveness returns in all treated dogs within 1.5-3 hours aftercessation of infusion and is comparable to that observed followingvehicle or propofol infusion. Etomidate, however, produces more profoundand durable adrenal suppression. The following day, all treatment groupsshowed a similar response to ACTH.

TABLE 3 Dosing regimen Time of ACTH bolus (mg/kg) + administrationinfusion after infusion Study (mg/kg/min) Test substance (hr) 1 3 + 0.75cyclopropyl-MOC- 0, 1.5, 2, 24 metomidate 2 + 0.15/0.10 etomidate 3 +0.75 vehicle 2 3 + 0.75 cyclopropyl-MOC- 1.5, 2, 24 metomidate 5 + 0.4 Propofol

For Study 1, the objectives were to evaluate the effects on adrenalresponsiveness after 120-minute infusions of cyclopropyl-MOC-metomidateor etomidate compared with vehicle. Drugs or vehicle were administeredas IV bolus followed by 120 minutes of continuous infusion to dogs inrandomized crossover designs. ACTH was administered at the end of theinfusion, as well as 90 and 180 minutes after the infusion, and bloodsamples were taken every 30-60 minutes to measure plasma cortisolconcentrations (by ELISA), as well as the concentrations ofcyclopropyl-MOC-metomidate and etomidate and their major metabolites.

Following vehicle administration, ACTH provoked a brisk increase in theplasma levels of cortisol that was quite variable among dogs. The secondand third ACTH stimuli provoked a further increase or maintenance ofelevated plasma cortisol levels. Following etomidate infusion,ACTH-induced increases in plasma cortisol were markedly inhibited andbegan to rise only with the third ACTH stimulus 180 minutes afterinfusion and never reached normal (>60% response seen in vehicle) duringthe 300-minute test period. For cyclopropyl-MOC-metomidate, cortisolresponse to the first ACTH stimulus was inhibited, but the response tothe second and third ACTH stimuli at 90 and 180 minute post-infusionwere robust and cortisol levels approached those observed post-vehicle.By 24 hours after infusion, each test substance groups exhibited similarACTH responses.

In Study 2, cyclopropyl-MOC-metomidate or propofol were infused for 120minutes, after dexamethasone suppression. All study methods describedfor Study 1 were repeated, except the ACTH administration at the end ofinfusion was omitted. Both groups responded in a similar fashion to ACTHchallenges given 90 and 180 minutes after the end of infusions, reachingnormal cortisol levels within 120 minutes after cessation of test drugadministration. Both test groups showed a normal response to ACTHchallenge the following day.

The pharmacokinetics of ABP-700 and its major metabolite, CPM-acid, wasstudied in rats following IV bolus injection and IV bolus followed byinfusion for 60 minutes.

Cyclopropyl-MOC-metomidate was administered to rats at IV bolus doses of4, 8, 12 & 16 mg/kg, and blood samples were taken at time points rangingfrom 30 seconds to 24 hours. Levels of cyclopropyl-MOC-metomidate andCPM-acid were determined using LC-MS or LC-MS/MS.Cyclopropyl-MOC-metomidate levels exhibited a rapid first-phase >10-folddecline during the first 5 minutes. This decline is at least partiallydue to rapid metabolism to CPM-acid, since it was present in the30-second samples at levels comparable to cyclopropyl-MOC-metomidate andcontinued to rise to reach a peak in the 12-minute samples. The firstphase of cyclopropyl-MOC-metomidate decline also presumably reflectsrapid tissue distribution, as indicated by the rapid onset of anesthesiafollowing IV bolus injection. Cyclopropyl-MOC-metomidate and CPM-acidexhibited secondary terminal elimination with half-lives ofapproximately 10 minutes and 20 minutes, respectively. Bothcyclopropyl-MOC-metomidate and CPM-acid were below the levels ofquantification (0.1 ng/mL and 5 ng/mL, respectively) in 24-hour PKsamples. No difference in cyclopropyl-MOC-metomidate PK was observedbetween male and female rats. Cyclopropyl-MOC-metomidate levels wereapproximately dose-proportional.

The PK profile of cyclopropyl-MOC-metomidate after continuous IVinfusion in rats was also examined. Rats first received an IV bolus of 4mg/kg to induce anesthesia followed by continuous infusion ofcyclopropyl-MOC-metomidate at 2 mg/kg/min or 4 mg/kg/min for 60 minutes.Blood samples were taken at time points ranging from 30 seconds to 24hours. Levels of cyclopropyl-MOC-metomidate and CPM-acid were determinedusing LC-MS or LC-MS/MS. Samples drawn 5, 30 or 60 minutes after thebeginning of continuous infusion indicated that levels of bothcyclopropyl-MOC-metomidate and CPM-acid rose gradually through theinfusion, appearing to approach steady state levels by 60-minute andwere approximately dose-proportional. During the first 30 minutesfollowing discontinuation of infusion, cyclopropyl-MOC-metomidate levelsexhibited a rapid ˜50-fold decline. This was followed by a slowersecondary phase of decline with a half-life of ˜20 minutes.

The pharmacokinetics of cyclopropyl-MOC-metomidate and its majormetabolite, CPM-acid, was studied in dogs following IV bolus injectionand IV bolus followed by continuous infusion for 60 minutes.

Cyclopropyl-MOC-metomidate was administered to dogs at IV bolus doses of0.25, 1, 2, 4, and 12 mg/kg, and blood samples were taken at time pointsranging from 30 seconds to 24 hours. Levels ofcyclopropyl-MOC-metomidate and CPM-acid were determined using LC-MS.Cyclopropyl-MOC-metomidate levels exhibited a rapid first-phase >10-folddecline during the first 5-10 minutes. Cyclopropyl-MOC-metomidate andCPM-acid exhibited secondary terminal elimination with half-lives indogs of approximately 5-10 minutes and 20-30 minutes, respectively. Bothcyclopropyl-MOC-metomidate and CPM-acid were below the levels ofquantification (0.1 ng/mL and 5 ng/mL, respectively) in 24-hour PKsamples. Cyclopropyl-MOC-metomidate levels were approximatelydose-proportional. No difference in cyclopropyl-MOC-metomidate PK wasobserved between male and female dogs.

The initial decline of cyclopropyl-MOC-metomidate is at least partiallydue to metabolism of cyclopropyl-MOC-metomidate to CPM-acid, since itwas present in the 30-second sample and continued to rise during thefirst 5-10 minutes. However, the rise in CPM-acid levels was initiallyslower than in rats, so the first phase of cyclopropyl-MOC-metomidatedecline also presumably reflects rapid tissue distribution, as indicatedby the rapid onset of anesthesia following IV bolus injection, followedby metabolism in a peripheral compartment(s).

Cyclopropyl-MOC-metomidate was also administered to dogs at 4 mg/kg IVbolus induction dose followed by continuous infusion of doses rangingfrom 0.5-4 mg/kg/min for 30-120 minutes. Blood samples were taken attime points ranging from 30 seconds to 24 hours. Levels ofcyclopropyl-MOC-metomidate and CPM-acid were determined using LC-MS orLC-MS/MS. Samples drawn 5, 30 or 60 minutes after the beginning ofcontinuous infusion indicated that levels of cyclopropyl-MOC-metomidatewere roughly constant during infusion, while levels of the CPM-acid,rose gradually through the infusion, appearing to approach steady statelevels by the 60-minute sample that were approximatelydose-proportional. During the first 10-30 minutes followingdiscontinuation of infusion, cyclopropyl-MOC-metomidate levels exhibiteda rapid ˜50-fold decline. This was followed by a slower secondary phaseof decline with a half-life of ˜20 minutes.

Predominant metabolism of cyclopropyl-MOC-metomidate to CPM-acid wasevident as CPM-acid reached concentrations approximately 10-fold higherthan cyclopropyl-MOC-metomidate by the end of infusion, and thendeclined following the infusion at a rate similar to the secondaryelimination of cyclopropyl-MOC-metomidate. Concentrations of bothcyclopropyl-MOC-metomidate and CPM-acid were near or below the levels ofquantification in 24-hour PK samples. Similar post-infusionpharmacokinetics were observed in a study with a 120-minute infusion at0.75 mg/kg/min.

Pharmacokinetic and toxicokinetic studies in rats and dogs confirm thatfollowing intravenous administration of cyclopropyl-MOC-metomidate, thedrug is both rapidly distributed to induce sedation/hypnosis, andrapidly metabolized to form CPM-acid. With both bolus and continuousinfusion administration, venous blood concentrations observed when ratsand dogs were sedated/anesthetized were greater than ˜250 ng/mL, or ˜0.8μM, consistent with the minimum concentrations that activated GABAreceptor/channels expressed in Xenopus oocytes by 10-20%. Followingbolus or discontinuation of infusion the levels ofcyclopropyl-MOC-metomidate fell quickly below this threshold, allowingrapid emergence from anesthesia and sedation. Second-phase eliminationwas rapid following bolus, but appeared to be somewhat prolongedfollowing more extended continuous infusion, particularly at high dose.Cyclopropyl-MOC-metomidate exposure increased in approximatelydose-proportional manner up to maximally tolerated doses/concentration,as outlined in Table 4.

TABLE 4 Dosing regimen Time of ACTH bolus (mg/kg) + administrationinfusion after infusion Study (mg/kg/min) Test substance (hr) 1 3 + 0.75cyclopropyl-MOC- 0, 1.5, 2, 24 metomidate 2 + 0.15/0.10 etomidate 3 +0.75 vehicle 2 3 + 0.75 cyclopropyl-MOC- 1.5, 2, 24 metomidate 5 + 0.4 Propofol *AUC estimates calculated by scaling from actual measurements.MED — minimum effective dose; MTD — maximum tolerated dose; C_(30sec) —blood concentration 30 seconds after bolus; C_(EOI) — bloodconcentration at end of infusion

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What is claimed is:
 1. A compound according to formula (I)

wherein, R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT; R² is R¹,optionally substituted linear or branched C₁-C₁₀ alkyl, optionallysubstituted linear or branched C₂-C₁₀ alkenyl, or optionally substitutedlinear or branched C₂-C₁₀ alkynyl, wherein the backbone of C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl optionally comprises one or moreheteroatoms; each R₃ is independently halogen, CN, CF₃, SR², SOR²,SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²; Z is N or CR⁶; R⁴,R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃, SR², SOR²,SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²; R⁷ and R⁸ areindependently hydrogen, optionally substituted linear or branched C₁-C₁₀alkyl, optionally substituted linear or branched C₂-C₁₀ alkenyl,optionally substituted linear or branched C₂-C₁₀ alkynyl, or R⁷ and R⁸together with the carbon they are attached to form an optionallysubstituted 3-8 membered cyclyl or heterocyclyl; R⁹ and R¹⁰ areindependently hydrogen, optionally substituted linear or branched C₁-C₁₀alkyl, optionally substituted linear or branched C₂-C₁₀ alkenyl,optionally substituted linear or branched C₂-C₁₀ alkynyl, optionallysubstituted C₄-C₈ cyclyl, optionally substituted C₃-C₈ heterocyclyl, orR⁹ and R¹⁰ together with the carbon they are attached to form anoptionally substituted 3-8 membered cyclyl or heterocyclyl, or R⁷ and R⁹together with the carbons they are attached to form an optionallysubstituted 3-8 membered cyclyl, heterocyclyl, aryl or heteroaryl; L¹and L² are independently a bond, optionally substituted linear orbranched C₁-C₁₀ alkylene, optionally substituted linear or branchedC₂-C₁₀ alkenylene, or optionally substituted linear or branched C₂-C₁₀alkynylene, wherein the backbone of C₁-C₁₀ alkylene, C₂-C₁₀ alkenylene,or C₂-C₁₀ alkynylene optionally comprises one or more heteroatoms; T isH, a linear or branched, substituted or unsubstituted C₁-C₁₀ alkyl,linear or branched, substituted or unsubstituted C₂-C₁₀ alkenyl, linearor branched, substituted or unsubstituted C₂-C₁₀ alkynyl, optionallysubstituted cyclyl, optionally substituted heterocylcyl, optionallysubstituted aryl, optionally substituted heteroaryl, or PEG, wherein thebackbone of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl optionallycomprises one or more heteroatoms; n is an integer from 0-5; and p is 0or 1, provided that at least one of R⁷, R⁸, R⁹ and R¹⁰ is not hydrogen,or a salt, solvate, or ester thereof.
 2. A compound according to formula(I)

wherein, R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT; R² is R¹ or alinear or branched, substituted or unsubstituted C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, or C₂-C₁₀ alkynyl, wherein backbone of C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, or C₂-C₁₀ alkynyl can contain one or more heteroatoms; each R₃is independently halogen, CN, CF₃, SR², SOR², SO₂R², OR², CO₂H, CO₂R²,N(R²)₂, NHR², NO₂, or R²; Z is N or CR⁵; R⁴, R⁵, and R⁶ areindependently hydrogen, halogen, CN, CF₃, SR², SOR², SO₂R², OR², CO₂H,CO₂R², N(R²)₂, NHR², NO₂, or R²; R⁷, R⁸, R⁹ and R¹⁰ are independentlyhydrogen, linear or branched, substituted or unsubstituted C₁-C₁₀ alkyl,linear or branched, substituted or unsubstituted C₂-C₁₀ alkenyl, linearor branched, substituted or unsubstituted C₂-C₁₀ alkynyl, or R⁷ and R⁸together with the carbon they are attached to form a 3-8 membered cyclylor heterocyclyl, or R⁹ and R¹⁰ together with the carbon they areattached to form a 3-8 membered cyclyl or heterocyclyl, provided that atleast one of R⁷, R⁸, R⁹ and R¹⁰ is not hydrogen, and wherein thebackbone of the C₁-C₂₀ alkylene, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀alkynyl can contain one or more heteroatoms; L¹ and L² are independentlya bond, a substituted or unsubstituted C₁-C₁₀ alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀ alkynylene, wherein backbone of alkylene cancontain one or more heteroatoms; T is H, a linear or branched,substituted or unsubstituted C₁-C₁₀ alkyl, linear or branched,substituted or unsubstituted C₂-C₁₀ alkenyl, linear or branched,substituted or unsubstituted C₂-C₁₀ alkynyl, optionally substitutedcyclyl, optionally substituted heterocylcyl, optionally substitutedaryl, optionally substituted heteroaryl, or PEG, wherein the backbone ofC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl can contain one or moreheteroatoms; n is an integer from 0-5; and p is 0 or
 1. 3. A compoundhaving a structure of formula (I):

wherein R¹ is L¹C(O)OL²-[C(R⁷R⁸)]_(p)—C(R⁹R¹⁰)—C(O)OT; R² is R¹ or alinear or branched, substituted or unsubstituted C₁-C₁₀alkyl,C₂-C₁₀alkenyl, or C₂-C₁₀alkynyl, wherein the backbone of C₁-C₁₀alkyl,C₂-C₁₀alkenyl, or C₂-C₁₀alkynyl optionally comprises one or moreheteroatoms; each R³ is independently halogen, CN, CF₃, SR², SOR²,SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²; Z is N or CR⁶; R⁴,R⁵, and R⁶ are independently hydrogen, halogen, CN, CF₃, SR², SOR²,SO₂R², OR², CO₂H, CO₂R², N(R²)₂, NHR², NO₂, or R²; R⁷ and R⁸ areindependently hydrogen, linear or branched, substituted or unsubstitutedC₁-C₁₀alkyl, C₂-C₁₀alkenyl, or C₂-C₁₀alkynyl, or R⁷ and R⁸ takentogether form an optionally substituted 3-8 membered carbocyclyl orheterocyclyl; R⁹ and R¹⁰ are independently hydrogen, optionallysubstituted C₄-C₈ cyclyl or optionally substituted C₃-C₈heterocyclyl,with the proviso that at least one of R⁹, and R¹⁰ is not hydrogen; or R⁷and R⁹ taken together form an optionally substituted 3-8 memberedcarbocyclyl, heterocyclyl, aryl, or heteroaryl; L¹ and L² areindependently a bond, a linear or branched, substituted or unsubstitutedC₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynylene; wherein thebackbone of C₁-C₁₀alkylene, C₂-C₁₀alkenylene, or C₂-C₁₀alkynyleneoptionally comprises one or more heteroatoms; T is hydrogen, linear orbranched, substituted or unsubstituted C₁-C₁₀alkyl, C₂-C₁₀alkenyl,C₂-C₁₀alkynyl, optionally substituted cyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, or PEG, wherein the backbone of C₁-C₁₀alkyl, C₂-C₁₀alkenyl,or C₂-C₁₀alkynyl optionally comprises one or more heteroatoms; each n isan integer of 0-5; and each p is 0 or 1, or a salt, solvate, or esterthereof.
 4. The compound of claim 1, having a structure of formula (IA):

or a salt, solvate, or ester thereof.
 5. The compound of claim 4,wherein Z is N.
 6. The compound of claim 4, wherein R⁴ and R⁵ are eachhydrogen.
 7. The compound of claim 4, wherein R⁹ and R¹⁰ together withthe carbon they are attached to form a 3-, 4-, 5, or 6- membered cyclyl.8. The compound of claim 4, wherein R⁹ and R¹⁰ together with the carbonthey are attached to form a 3-, 4-, 5, or 6- membered heterocyclyl. 9.The compound of claim 4, wherein R² is methyl, ethyl, n-propyl,isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, neopentyl,hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, or2,2-dimethylbutyl.
 10. The compound of claim 4, wherein T is methyl orethyl.
 11. The compound of claim 1, having a structure of formula (IB):

or a salt, solvate, or ester thereof.
 12. The compound of claim 11,wherein Z is N.
 13. The compound of claim 11, wherein R⁴ and R⁵ are eachhydrogen.
 14. The compound of claim 11, wherein R⁹ and R¹⁰ together withthe carbon they are attached to form a 3-, 4-, 5, or 6- membered cyclyl.15. The compound of claim 11, wherein R⁹ and R¹⁰ together with thecarbon they are attached to form a 3-, 4-, 5, or 6- memberedheterocyclyl.
 16. The compound of claim 11, wherein R² is methyl, ethyl,n-propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl,neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, or2,2-dimethylbutyl.
 17. The compound of claim 11, wherein T is methyl orethyl.
 18. The compound of claim 1, having a structure of formula (IC):

or a salt, solvate, or ester thereof.
 19. The compound of claim 18,wherein Z is N.
 20. The compound of claim 18, wherein R⁴ and R⁵ are eachhydrogen.
 21. The compound of claim 18, wherein R⁹ and R¹⁰ together withthe carbon they are attached to form a 3-, 4-, 5, or 6- membered cyclyl.22. The compound of claim 18, wherein R⁹ and R¹⁰ together with thecarbon they are attached to form a 3-, 4-, 5, or 6- memberedheterocyclyl.
 23. The compound of claim 18, wherein R² is methyl, ethyl,n-propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl,neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, or2,2-dimethylbutyl.
 24. The compound of claim 18, wherein T is methyl orethyl.
 25. The compound of claim 1, wherein the compound of formula (I)is selected from the group consisting of

or a salt, solvate, or ester thereof.
 26. The compound of claim 1,wherein the compound of formula (I) is selected from the groupconsisting of

or a salt, solvate, or ester thereof.
 27. The compound of claim 1,having a structure selected from the group consisting of

or a salt, solvate, or ester thereof.
 28. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 29. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 30. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 31. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 32. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 33. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 34. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.
 35. The compound of claim 1,having a structure:

or a salt, solvate, or ester thereof.